Targeting cathepsin S promotes activation of OLF1-BDNF/TrkB axis to enhance cognitive function.

BACKGROUND: Cathepsin S (CTSS) is a cysteine protease that played diverse roles in immunity, tumor metastasis, aging and other pathological alterations. At the cellular level, increased CTSS levels have been associated with the secretion of pro-inflammatory cytokines and disrupted the homeostasis of Ca2+ flux. Once CTSS was suppressed, elevated levels of anti-inflammatory cytokines and changes of Ca2+ influx were observed. These findings have inspired us to explore the potential role of CTSS on cognitive functions. METHODS: We conducted classic Y-maze and Barnes Maze tests to assess the spatial and working memory of Ctss-/- mice, Ctss+/+ mice and Ctss+/+ mice injected with the CTSS inhibitor (RJW-58). Ex vivo analyses including long-term potentiation (LTP), Golgi staining, immunofluorescence staining of sectioned whole brain tissues obtained from experimental animals were conducted. Furthermore, molecular studies were carried out using cultured HT-22 cell line and primary cortical neurons that treated with RJW-58 to comprehensively assess the gene and protein expressions. RESULTS: Our findings reported that targeting cathepsin S (CTSS) yields improvements in cognitive function, enhancing both working and spatial memory in behavior models. Ex vivo studies showed elevated levels of long-term potentiation levels and increased synaptic complexity. Microarray analysis demonstrated that brain-derived neurotrophic factor (BDNF) was upregulated when CTSS was knocked down by using siRNA. Moreover, the pharmacological blockade of the CTSS enzymatic activity promoted BDNF expression in a dose- and time-dependent manner. Notably, the inhibition of CTSS was associated with increased neurogenesis in the murine dentate gyrus. These results suggested a promising role of CTSS modulation in cognitive enhancement and neurogenesis. CONCLUSION: Our findings suggest a critical role of CTSS in the regulation of cognitive function by modulating the Ca2+ influx, leading to enhanced activation of the BDNF/TrkB axis. Our study may provide a novel strategy for improving cognitive function by targeting CTSS.

Melatonin alleviates endoplasmic reticulum stress and follicular granulosa cell apoptosis by regulating ATF4 to activate mTOR signaling pathway in chickens.

Follicular atresia in chickens reduces the number of follicles that can further develop, leading to decrease egg laying. Endoplasmic reticulum stress (ERS) can initiate a unique pathway inducing the apoptosis of follicular granulosa cells, thus reducing egg laying. Melatonin (MEL) is involved in the regulation of follicle development, ovulation, and oocyte maturation, and is closely related to follicle fate. Mammalian target of Rapamycin (mTOR) signaling pathway plays an important role in cell growth regulation, and that there is a possible crosstalk between melatonin and mTOR activity in granular cells maturation and ovulation. This study aimed to investigate whether MEL inhibits ERS and follicular granulosa cell apoptosis by regulating ATF4 to activate mTOR signaling pathway in chickens. Frist, we established an in vitro ERS cell model using tunicamycin (TM). The results showed that different concentrations of TM exhibited dose-dependent inhibition of cell activity and induction of granulosa cells (P<0.01). Therefore, we chose 5 µg/mL of TM and a treatment time for 6 h as the optimal concentration for the following experiments. Then we investigate whether melatonin can inhibit ERS. TM treatment decreased the cell viability and Bcl-2 expression, increasing ROS levels and the mRNA expression of Grp78, ATF4, CHOP, PERK, eIF-2α, and BAX (P<0.01), whereas TM+MEL treatment significantly inhibited these changes (P<0.01). Then we explored whether melatonin protects follicular granulosa cells from ERS-induced apoptosis through the mammalian target of rapamycin (mTOR) signaling pathway by regulating ATF4, we found that ATF4 knockdown inhibited ERS by decreasing the expression of ERS-related genes and proteins and activating mTOR signaling pathway by increasing the protein expression of p4E-BP1 and pT389-S6K (P<0.001), while these changes were promoted by TM+si-ATF4+MEL treatment (P<0.01). These results indicate that MEL could alleviate TM-induced ERS by regulating ATF4 to activate mTOR signaling pathway in follicular granulosa cells, thus providing a new perspective for prolonging the laying cycle in chickens.

Melatonin alleviates endoplasmic reticulum stress to improve ovarian function by regulating the mTOR pathway in aged laying hens.

Granular cell apoptosis is a key factor leading to follicular atresia and decreased laying rate in aged laying hens. Endoplasmic reticulum stress (ERS) induced cell apoptosis is a new type of apoptosis pathway. Previous studies have shown that the ERS pathway is involved in the regulation of follicular development and atresia, and can be regulated by mTOR. Melatonin (MEL) can protect the normal development of follicles, but the precise mechanism by which MEL regulates follicular development is not yet clear. So, we investigated the potential relationship between MEL and ERS and mTOR signaling pathway in vivo through intraperitoneal injection of MEL in aged laying hens. The results show that the laying rate, ovarian follicle number, plasma MEL, E2, LH, FSH concentrations, as well as the mRNA expression of mTOR signaling-associated genes TSC1, TSC2, mTOR, 4E-BP1, and S6K in old later-period chicken control (Old-CN) group was significantly decreased (P < 0.01). In contrast, the ERS-related of plasma and granular cell layer mRNA expression of Grp78, CHOP, and Caspase-3 was significantly increased (P < 0.01). While both of the effects were reversed by MEL. Then, aging granulosa cells were treated with MEL in vitro, followed by RNA seq analysis, and it was found that 259 and 322 genes were upregulated and downregulated. After performing GO enrichment analysis, it was found that DEGs significantly contribute to the biological processes including cell growth and apoptosis. Using pathway enrichment analysis, we found significant overrepresentation of cellular processes related to mTOR signaling and endoplasmic reticulum (ER) stress, involving genes such as GRB10, SGK1, PRKCA, RPS6KA2, RAF1, PIK3R3, FOXO1, DERL3, HMOX1, TLR7, VAMP7 and INSIG2. The obtained results of RT-PCR showed consistency with the RNA-Seq data. In summary, the underlined results revealed that MEL has significantly contributed to follicular development via activating the mTOR signaling pathway-related genes and alleviating ERS-related genes in laying hens. The current study provides a theoretical background for enhancing the egg-laying capability of hens and also providing a basis for elucidating the molecular mechanism of follicular selection.

Targeting the chromatin binding of exportin-1 disrupts NFAT and T cell activation.

Exportin-1 (XPO1/CRM1) plays a central role in the nuclear-to-cytoplasmic transport of hundreds of proteins and contributes to other cellular processes, such as centrosome duplication. Small molecules targeting XPO1 induce cytotoxicity, and selinexor was approved by the Food and Drug Administration in 2019 as a cancer chemotherapy for relapsed multiple myeloma. Here, we describe a cell-type-dependent chromatin-binding function for XPO1 that is essential for the chromatin occupancy of NFAT transcription factors and thus the appropriate activation of T cells. Additionally, we establish a class of XPO1-targeting small molecules capable of disrupting the chromatin binding of XPO1 without perturbing nuclear export or inducing cytotoxicity. This work defines a broad transcription regulatory role for XPO1 that is essential for T cell activation as well as a new class of XPO1 modulators to enable therapeutic targeting of XPO1 beyond oncology including in T cell-driven autoimmune disorders.

Hollow Hafnium Oxide (HfO2) Fibers: Using an Effective Combination of Sol-Gel, Electrospinning, and Thermal Degradation Pathway.

In recent years, hafnium oxide (HfO2) has gained increasing interest because of its high dielectric constant, excellent thermal stability, and high band gap. Although HfO2 bulk and film materials have been prepared and well-studied, HfO2 fibers, especially hollow fibers, have been less investigated. In this study, we present a facile preparation method for HfO2 hollow fibers through a unique integration of the sol-gel process and electrospinning technique. Initially, polystyrene (PS) fibers are fabricated by using electrospinning, followed by dipping in a HfO2 precursor solution, resulting in HfO2-coated PS fibers. Subsequent thermal treatment at 800 °C ensures the selective pyrolysis of the PS fibers and complete condensation of the HfO2 precursors, forming HfO2 hollow fibers. Scanning electron microscopy (SEM) characterizations reveal HfO2 hollow fibers with rough surfaces and diminished diameters, a transformation attributed to the removal of the PS fibers and the condensation of the HfO2 precursors. Our study also delves into the influence of precursor solution molar ratios, showcasing the ability to achieve smaller HfO2 fiber diameters with reduced precursor quantities. Validation of the material composition is achieved through thermogravimetric analysis (TGA) and energy-dispersive spectroscopy (EDS) mapping. Additionally, X-ray diffraction (XRD) analysis provides insights into the crystallinity of the HfO2 hollow fibers, highlighting a higher crystallinity in fibers annealed at 800 °C compared with those treated at 400 °C. Notably, the HfO2 hollow fibers demonstrate a water contact angle (WCA) of 38.70 ± 5.24°, underscoring the transformation from hydrophobic to hydrophilic properties after the removal of the PS fibers. Looking forward, this work paves the way for extensive research on the surface properties and potential applications of HfO2 hollow fibers in areas such as filtration, energy storage, and memory devices.

Physical Activity Intervention for Urban Black Women With Asthma: Protocol for a Randomized Controlled Efficacy Study.

BACKGROUND: Black women experience a higher prevalence of poor asthma outcomes and physical inactivity than their White counterparts. Black women comprise a particularly vulnerable group of patients with asthma, with some of the highest rates of asthma in adults, high health care use (emergency department visits and hospitalizations), and the highest crude asthma mortality rate of all race or ethnicity groups. Despite recommendations to engage in regular physical activity, fewer than 15% of Black women meet the 2008 National Physical Activity Guidelines, the lowest of all racial subgroups of adults. Given the connection between physical inactivity and poor asthma outcomes, addressing physical activity among Black women with asthma is imperative. OBJECTIVE: This 2-arm randomized controlled trial aims to (1) determine the efficacy of a lifestyle walking intervention on asthma control compared to an education (control) group over 24 weeks, (2) examine the maintenance effects of the lifestyle walking intervention on asthma control at 48 weeks, (3) explore the behavioral mediators (eg, self-efficacy, social support, self-regulation, and daily physical activity levels) and contextual moderators (eg, baseline asthma severity, neighborhood environment, comorbid conditions, and social determinants of health) that contribute to treatment responsiveness, and (4) assess the reach and implementation potential of the intervention. METHODS: The proposed study (ACTION [A Lifestyle Physical Activity Intervention for Minority Women with Asthma]) delivers a 24-week lifestyle walking intervention designed for and by urban Black women with asthma. Participants (n=224) will be recruited through 2 urban health care systems that care for a diverse Black population. Patients will be randomized to one of two groups: (1) ACTION intervention (group sessions, physical activity self-monitoring-Fitbit, and text-based support for step goal setting) or (2) education control (an individual asthma education session and SMS text messages related to asthma education). Outcome assessments will take place at baseline, 12, 24, and 48 weeks. The primary outcome is a change in asthma control from baseline to week 24 as assessed by the asthma control questionnaire-6 (ACQ-6). Secondary outcomes include asthma-related quality of life, health care use, and asthma exacerbations and behavioral outcomes such as self-efficacy, self-regulation, social support, and physical activity. RESULTS: This study was funded by the National Institute of Minority Health Disparities in August 2022. We pilot-tested our recruitment and intervention procedures and began recruitment in April 2023, with the enrollment of our first participant in May 2023. The anticipated completion of the study is April 2027. CONCLUSIONS: This study will deliver a new approach to physical activity interventions in Black women with asthma and help to provide guidance for addressing physical activity within this subgroup. This study will also provide a potential framework for future studies in minoritized populations with other disease conditions associated with low levels of physical activity. TRIAL REGISTRATION: ClinicalTrials.gov NCT05726487; https://clinicaltrials.gov/study/NCT05726487. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/55700.

Recombinant Deoxyribonuclease I Eye Drops for Ocular Graft Versus Host Disease: Results of a Randomized Clinical Trial.

OBJECTIVE: We have previously shown that neutrophil extracellular traps (NETs) are present on the ocular surface of patients with ocular graft versus host disease (oGVHD), contributing to inflammation and surface disease. Therefore, we performed a clinical trial using deoxyribonuclease I (DNAase) eye drops to test the hypothesis that reducing the abundance of NETs from the ocular surface will reduce signs and symptoms of oGVHD. METHODS: A prospective, phase I or II, randomized, placebo-controlled, double-masked clinical trial was performed to determine the safety and preliminary efficacy of DNAase (0.1%) eye drops four times daily for 8 weeks in patients with oGVHD (n=58). Intent-to-treat analysis was performed to determine the change in safety outcome measures (drug tolerability and proportion of adverse events) and efficacy outcome measures (ocular surface disease index [OSDI] score and corneal staining) between baseline and week 8. RESULTS: Tolerability and adverse events were similar in the vehicle and DNAase groups. Within the DNAase group (but not the vehicle group), corneal staining showed a statistically significant and clinically meaningful reduction at week 8 (3.50 [2.75; 5.00]) compared with baseline (5.00 [3.00; 7.00]). The OSDI score also showed a statistically significant clinically meaningful reduction of 18.4 (9.16; 33.1) ( P <0.001) at week 8 compared with baseline (45.5 [31.8; 50.0]) within the DNAase group. The proportion of eyes that had improvement in subjective global assessment (SGA) and mucous discharge was significantly greater in the DNAase group (55.6% and 57.7% at weeks 4 and 8, respectively; P <0.0001 at both time points) as compared with the vehicle group (35.7% and 34.0% at weeks 4 and 8, respectively). CONCLUSIONS: Treatment of patients with oGVHD using DNAase eye drops is safe and demonstrates preliminary efficacy. Deoxyribonuclease I eye drops can potentially reduce the severity of signs and symptoms of ocular surface disease in patients with oGVHD.

Guard Cell-Inspired Ion Channels: Harnessing the Photomechanical Effect via Supramolecular Assembly of Cross-Linked Azobenzene/Polymers.

Stimuli-responsive ion nanochannels have attracted considerable attention in various fields because of their remote controllability of ionic transportation. For photoresponsive ion nanochannels, however, achieving precise regulation of ion conductivity is still challenging, primarily due to the difficulty of programmable structural changes in confined environments. Moreover, the relationship between noncontact photo-stimulation in nanoscale and light-induced ion conductivity has not been well understood. In this work, a versatile design for fabricating guard cell-inspired photoswitchable ion channels is presented by infiltrating azobenzene-cross-linked polymer (AAZO-PDAC) into nanoporous anodic aluminum oxide (AAO) membranes. The azobenzene-cross-linked polymer is formed by azobenzene chromophore (AAZO)-cross-linked poly(diallyldimethylammonium chloride) (PDAC) with electrostatic interactions. Under UV irradiation, the trans-AAZO isomerizes to the cis-AAZO, causing the volume compression of the polymer network, whereas, in darkness, the cis-AAZO reverts to the trans-AAZO, leading to the recovery of the structure. Consequently, the resultant nanopore sizes can be manipulated by the photomechanical effect of the AAZO-PDAC polymers. By adding ionic liquids, the ion conductivity of the light-driven ion nanochannels can be controlled with good repeatability and fast responses (within seconds) in multiple cycles. The ion channels have promising potential in the applications of biomimetic materials, sensors, and biomedical sciences.

Role of microbiota in radiation-induced small-bowel damage.

Radiation-induced gastrointestinal damage is a common acute radiation syndrome. Previous studies have highlighted that Galectin-1 and Interleukin-6 (IL-6) are associated with flaking of small intestinal villi and intestinal radioresistance. Therefore, our goal is to study whether gut bacteria regulated by galectin-1 or IL-6 can mitigate radiation-induced small intestine damage. In this study, differences between galectin-1, sgp130-regulated and wild-type (WT) mice were analyzed by microbiome array. The effects of the Firmicutes/Bacteroidetes (F/B) ratio and the proportion of bacterial distribution at the phylum level were observed after 18 Gy whole abdomen radiation. Fecal microbiota transplantation was used to implant radioresistant gut flora into WT mice, and the number of viable small intestinal crypt foci was observed by immunohistochemistry. Fecal transplantation from galectin-1 knockout and sgp130 transgenic mice, with higher radiation resistance, into WT mice significantly increased the number of surviving small intestinal crypts. This radiation resistance, generated through gene regulation, was not affected by the F/B ratio. We initially found that the small intestinal villi of WT mice receiving radioresistant mouse fecal bacteria demonstrated better repair outcomes after radiation exposure. These results indicate the need for a focus on the identification and application of superior radioresistant bacterial strains. In our laboratory, we will further investigate specific radioresistant bacterial strains to alleviate acute side effects of radiation therapy to improve the patients' immune ability and postoperative quality of life.

Discovery of novel coumarin-based derivatives as inhibitors of tubulin polymerization targeting the colchicine binding site with potent anti-gastric cancer activities.

In this work, a series of novel coumarin-based derivatives were designed and synthesized as tubulin polymerization inhibitors targeting the colchicine binding site, and their antiproliferative activities against MGC-803, HCT-116 and KYSE30 cells were evaluated. Among them, the compound I-3 (MY-1442) bearing a 6-methoxy-1,2,3,4-tetrahydroquinoline group exhibited most potent inhibitory activities on MGC-803 (IC50 = 0.034 µM), HCT-116 (IC50 = 0.081 µM) and KYSE30 cells (IC50 = 0.19 µM). Further mechanism studies demonstrated that compound I-3 (MY-1442) could directly bind to the colchicine binding site of ß-tubulin to inhibit tubulin polymerization and microtubules at the cellular level. The results of molecular docking indicated there were well binding interactions between compound I-3 (MY-1442) and the colchicine binding site of ß-tubulin. Compound I-3 (MY-1442) also exhibited effective anti-proliferation, pro-apoptosis, and anti-migration abilities against gastric cancer cells MGC-803. Additionally, compound I-3 (MY-1442) could regulate the expression of cell cycle- and apoptosis-related proteins. Importantly, compound I-3 (MY-1442) could significantly inhibit tumor growth in the MGC-803 xenograft tumor model with a TGI rate of 65.5 % at 30 mg/kg/day. Taken together, this work suggested that the coumarin skeleton exhibited great potential to be a key pharmacophore of tubulin polymerization inhibitors for the discovery of anticancer agents.

Radiofrequency ablation for thyroid Bethesda III nodules: preliminary results.

Purpose: The purpose of this study was to evaluate the feasibility of radiofrequency ablation (RFA) for thyroid nodules with cytological atypia of undetermined significance or follicular lesion of undetermined significance (AUS/FLUS, Bethesda III). Materials and methods: A total of 28 adults presenting with 30 initial Bethesda III nodules underwent thyroid RFA at a single medical center. Thyroid nodules with Bethesda IV or V according to the second aspiration were excluded. All RFA procedures were performed using the free-hand, 'moving-shot' technique under local anesthesia. Clinical features and demographics, RFA details, nodule volume reduction rate (VRR), and complications were analyzed. Results: The mean age of patients was 47.6 years, 82.1% of whom were females. Mean nodule volumes at pre-RFA, and at 6 months and 12 months post-RFA were 7.92, 2.42, and 1.25 mL, respectively, with a VRR of 77.9% at 6 months, and 87.4% at 12 months. Post-RFA complications were noted in two patients, one with transient vocal cord palsy and another with isthmus minor rupture. Conclusion: RFA may be another safe alternative except for active surveillance or surgical excision for AUS/FLUS nodules with low-suspicion Thyroid Imaging Reporting and Data System features for patients who are unsuitable or strongly refuse surgery. Long-term results remain uncertain, thus further follow-up study is necessary.

[Clinical and immunological features of primary Sjögren's syndrome patients with positive anti-centromere protein B antibody].

OBJECTIVE: To investigate the clinical and immunological features of primary Sjögren's syndrome (pSS) patients with positive anti-centromere protein B (CENP-B) antibody. METHODS: In this cross-sectional study, the general clinical data, radiographic examination and labial salivary gland biopsy data, and serum immunological and biochemical data of patients diagnosed with pSS from January 2016 to August 2022 were evaluated. The included patients were divided into the anti-CENP-B antibody positive and negative groups. Intergroup differences were analyzed with SPSS 23.0 software. Subgroup analysis was further performed by dividing the anti-CENP-B antibody positive group into the single anti-CENP-B antibody positive and with other auto-antibodies positive groups to determine the characters related to anti-CENP-B antibody. RESULTS: In this study, 288 patients with pSS were evaluated, including 75 patients with anti-CENP-B antibody positive and 213 with anti-CENP-B antibody negative. Univariate analysis showed that compared with the anti-CENP-B antibody negative group, the patients of the anti-CENP-B antibody positive group were older, had lower proportion of the patients with salivary gland enlargement and higher proportion of autoimmune liver disease. As for immunological indicators, the positive proportions of anti-SSA/Ro60, anti-Ro52, and anti-SSB antibodies were significantly lower. Moreover, the immunoglobulin (Ig) G and rheumatoid factor levels were significantly lower, while the IgM level was significantly higher in the patients of the anti-CENP-B antibody positive group. As for serum biochemical indicators, for the patients of the anti-CENP-B antibody positive group, the level of total protein (TP) was lower, the albumin/globulin ratio was higher, and the levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma glutamyl transferase (GGT), lactate dehydrogenase (LDH) were higher. Subgroup analysis showed that the levels of TP and IgA in the patients of the single anti-CENP-B antibody positive group were significantly lower than those of the patients with other autoantibodies positive group. CONCLUSION: The pSS patients with anti-CENP-B antibody positive have unique clinical and immunological features of lower disease activity, less likely to involve salivary gland, higher risk for autoimmune liver disease, and higher levels of liver function indicators. Anti-CENP-B antibody may be a marker for a distinct subset of polyautoimmunity in Sjögren's syndrome.

Radiofrequency ablation for thyroid Bethesda III nodules: preliminary results.

Purpose: The purpose of this study was to evaluate the feasibility of radiofrequency ablation (RFA) for thyroid nodules with cytological atypia of undetermined significance or follicular lesion of undetermined significance (AUS/FLUS, Bethesda III). Materials and methods: A total of 28 adults presenting with 30 initial Bethesda III nodules underwent thyroid RFA at a single medical center. Thyroid nodules with Bethesda IV or V according to the second aspiration were excluded. All RFA procedures were performed using the free-hand, 'moving-shot' technique under local anesthesia. Clinical features and demographics, RFA details, nodule volume reduction rate (VRR), and complications were analyzed. Results: The mean age of patients was 47.6 years, 82.1% of whom were females. Mean nodule volumes at pre-RFA, and at 6 months and 12 months post-RFA were 7.92, 2.42, and 1.25 mL, respectively, with a VRR of 77.9% at 6 months, and 87.4% at 12 months. Post-RFA complications were noted in two patients, one with transient vocal cord palsy and another with isthmus minor rupture. Conclusion: RFA may be another safe alternative except for active surveillance or surgical excision for AUS/FLUS nodules with low-suspicion Thyroid Imaging Reporting and Data System features for patients who are unsuitable or strongly refuse surgery. Long-term results remain uncertain, thus further follow-up study is necessary.

Access to restorative oral health care for children living in Illinois with Medicaid vs private dental insurance: An audit study.

BACKGROUND: Public dental insurance programs for children aim to provide access to care, but barriers remain that preclude care delivery. Understanding these barriers is an important health policy concern. METHODS: A telephone audit sought to ascertain availability of oral health care for children in dental offices eligible to bill Medicaid. Female callers posing as mothers called eligible offices requesting appointments. In this cross-over design, offices were randomized to public or private insurance for initial calls and then to the other condition after a washout period. RESULTS: Using mixed models, privately insured patients had 5.9 times (95% CI, 4.55 to 7.69) greater odds of obtaining an appointment than Medicaid patients. Compared with patients in Cook County, suburban patients had slightly better odds, whereas nonurban patients in larger and smaller rural counties had lower odds of success. CONCLUSIONS: Medicaid compares poorly with private insurance for providing access to pediatric oral health care. Regardless of insurance conditions, access is poor in less urban environments compared with metropolitan communities. PRACTICAL IMPLICATIONS: Even Medicaid-enrolled dental practices limit the care they extend to insured children. Providing Medicaid by itself cannot overcome large oral health care access disparities, which are greatest in rural communities.

Boosting Ion Conductivities: Light-Modulated Azobenzene-Based Ionic Liquids in Vertical Nanochannels.

Exploring stimuli-responsive ion-conductive materials is a challenging task, but it has gained increasing attention because of their enormous potential applications in actuators, sensors, and smart electronics. Here, we demonstrate a distinctive photoresponsive ion-conductive device that utilizes azobenzene-based ionic liquids ([AzoCnMIM][Br], where n = 2, 6, and 10), confined in nanochannels of anodic aluminum oxide (AAO) templates for photoisomerization. The structure of [AzoCnMIM][Br] comprises photoresponsive and hydrophobic azobenzene moieties, hydrophilic imidazolium cations, and negatively charged bromide ions. Therefore, [AzoCnMIM][Br] can form micelles and exhibit photoresponsive ion conductivities. The nanochannels of AAO templates exhibit a confinement effect on the formation of azobenzene-based ionic liquid micelles due to the pore size, thereby preventing the formation of larger micelles that could lead to a decrease in conductivity. Consequently, the ion conductivities of the azobenzene-based ionic liquids are higher in the nanochannels of the AAO templates. The effects of the length of carbon chains on the azobezene-based ionic liquids and the pore size of the AAO templates have also been investigated. Additionally, through irradiation with UV/vis light, [AzoCnMIM][Br] can undergo reversible isomerization, thereby reversibly changing the sizes of the micelles and subsequently altering the ion conductivities.

Coordinated Health Care Interventions for Childhood Asthma Gaps in Outcomes (CHICAGO) plan.

Background: Evidence-based strategies to improve outcomes in minority children with uncontrolled asthma discharged from the emergency department (ED) are needed. Objectives: This multicenter pragmatic clinical trial was designed to compare an ED-only intervention (decision support tool), an ED-only intervention and home visits by community health workers for 6 months (ED-plus-home), and enhanced usual care (UC). Methods: Children aged 5 to 11 years with uncontrolled asthma were enrolled. The change over 6 months in the Patient-Reported Outcomes Measurement Information System Asthma Impact Scale score in children and Satisfaction with Participation in Social Roles score in caregivers were the primary outcomes. The secondary outcomes included guideline-recommended ED discharge care and self-management. Results: Recruitment was significantly lower than expected (373 vs 640 expected). Of the 373 children (64% Black and 31% Latino children), only 63% completed the 6-month follow-up visit. In multivariable analyses that accounted for missing data, the adjusted odds ratios and 98% CIs for differences in Asthma Impact Scores or caregivers' Satisfaction with Participation in Social Roles scores were not significant. However, guideline-recommended ED discharge care was significantly improved in the intervention groups versus in the UC group, and self-management behaviors were significantly improved in the ED-plus-home group versus in the ED-only and UC groups. Conclusions: The ED-based interventions did not significantly improve the primary clinical outcomes, although the study was likely underpowered. Although guideline-recommended ED discharge care and self-management did improve, their effect on clinical outcomes needs further study.

Melatonin alleviates ovarian function damage and oxidative stress induced by dexamethasone in the laying hens through FOXO1 signaling pathway.

Oxidative stress can trigger follicular atresia, and decrease follicles quantity in each development stage, thereby alleviating reproductive activity. The induction of oxidative stress in chickens through intraperitoneal injection of dexamethasone is a reliable and stable method. Melatonin has been shown to mitigate oxidative stress in this model, but the underlying mechanism remains unclear. Therefore, this study aimed to investigate whether melatonin can recover aberrant antioxidant status induced by dexamethasone and the specific mechanism behind melatonin-dependent protection. A total of 150 healthy 40-wk-old Dawu Jinfeng laying hens with similar body weights and laying rates were randomly divided into three groups, with five replicates per group and 10 hens per replicate. The hens in the control group (NS) received intraperitoneal injections of normal saline for 30 d, the dexamethasone group (Dex+NS) received 20 mg/kg dose of dexamethasone for the first 15 d, followed by the 15 d of normal saline treatment. While in the melatonin group (Dex+Mel), dexamethasone (20 mg/kg dose) was injected intraperitoneally in the first 15 d, and melatonin (20 mg/kg/d) was injected in the last 15 d. The results showed that dexamethasone treatment significantly enhanced oxidative stress (P < 0.05), while melatonin not only inhibited the oxidative stress but also notably enhanced the antioxidant enzymes superoxide dismutase (SOD), catalase activity (CAT), glutathione peroxidase (GSH-Px), and antioxidant genes CAT, superoxide dismutase 1 (SOD1), glutathione peroxidase 3 (GPX3), and recombinant peroxiredoxin 3 (PRDX3) expression (P < 0.05). Melatonin treatment also markedly reduced 8-hydroxy deoxyguanosine (8-OHdG), malondialdehyde (MDA), and reactive oxygen species (ROS) levels (P < 0.05) and apoptotic genes Caspase-3, Bim, and Bax in the follicle. In the Dex+Mel group, the Bcl-2 and SOD1 protein levels were also increased (P < 0.05). Melatonin inhibited the forkhead Box Protein O1 (FOXO1) gene and its protein expression (P < 0.05). In general, this investigation revealed that melatonin might decrease oxidative stress and ROS by enhancing antioxidant enzymes and genes, activating the antiapoptotic genes, and inhibiting the FOXO1 pathway in laying hens.

Cooperative sensing of mitochondrial DNA by ZBP1 and cGAS promotes cardiotoxicity.

Mitochondrial DNA (mtDNA) is a potent agonist of the innate immune system; however, the exact immunostimulatory features of mtDNA and the kinetics of detection by cytosolic nucleic acid sensors remain poorly defined. Here, we show that mitochondrial genome instability promotes Z-form DNA accumulation. Z-DNA binding protein 1 (ZBP1) stabilizes Z-form mtDNA and nucleates a cytosolic complex containing cGAS, RIPK1, and RIPK3 to sustain STAT1 phosphorylation and type I interferon (IFN-I) signaling. Elevated Z-form mtDNA, ZBP1 expression, and IFN-I signaling are observed in cardiomyocytes after exposure to Doxorubicin, a first-line chemotherapeutic agent that induces frequent cardiotoxicity in cancer patients. Strikingly, mice lacking ZBP1 or IFN-I signaling are protected from Doxorubicin-induced cardiotoxicity. Our findings reveal ZBP1 as a cooperative partner for cGAS that sustains IFN-I responses to mitochondrial genome instability and highlight ZBP1 as a potential target in heart failure and other disorders where mtDNA stress contributes to interferon-related pathology.

Smart Temperature-Gating and Ion Conductivity Control of Grafted Anodic Aluminum Oxide Membranes.

Over the past few decades, stimuli-responsive materials have been widely applied to porous surfaces. Permeability and conductivity control of ions confined in nanochannels modified with stimuli-responsive materials, however, have been less investigated. In this work, the permeability and conductivity control of ions confined in nanochannels of anodic aluminum oxide (AAO) templates modified with thermo-responsive poly(N-isopropylacrylamide) (PNIPAM) brushes are demonstrated. By surface-initiated atom transfer radical polymerization (SI-ATRP), PNIPAM brushes are successfully grafted onto the hexagonally packed cylindrical nanopores of AAO templates. The surface hydrophilicities of the membranes can be reversibly altered because of the lower critical solution temperature (LCST) behavior of the PNIPAM polymer brushes. From electrochemical impedance spectroscopy (EIS) analysis, the temperature-gating behaviors of the AAO-g-PNIPAM membranes exhibit larger impedance changes than those of the pure AAO membranes at higher temperatures because of the aggregation of the grafted PNIPAM chains. The reversible surface properties caused by the extended and collapsed states of the polymer chains are also demonstrated by dye release tests. The smart thermo-gated and ion-controlled nanoporous membranes are suitable for future smart membrane applications.

Label-free detection of MiRNA biomarkers using broadband multi-resonant infrared metasurfaces for early breast cancer diagnosis.

Breast cancer is the most prevalent cancer globally. Early detection is crucial and can be achieved by detecting cancer biomarkers in blood, such as circulating miRNAs (microRNAs). In this study, we present a label-free detection method based on broadband multi-resonant infrared metasurface for surface-enhanced infrared absorption (SEIRA) spectroscopy to detect miRNAs. The SEIRA resonances were optimized to match the miRNA biomarker fingerprint regions in the range of 800 to 2000 cm-1 and 2800 to 3500 cm-1, resulting in a simulated resonance enhancement of up to 103 times. Nine patient samples (six cancerous and three non-cancerous) were measured using SEIRA multi-well sensor chips. A novel analysis method, SEIRA-AR, was also developed to benchmark the results against industry standards, such as quantitative reverse transcription polymerase chain reaction (RT-qPCR) and next-generation sequencing (NGS). Our results showed an excellent linear correlation with a Pearson's r value of up to 0.99 and an R Squared value of up to 0.98. This study represents the first use of a SEIRA sensor for biomarker detection on clinical breast cancer samples and introduces an analysis method that produces results comparable to industry standards. Our findings pave the way for routine cancer diagnosis in the future. Additionally, the method discussed can be generalized to other biosensing activities involving two-step binding processes with complementary molecule-capturing agents.