Comprehensive Multi-omics Analysis Reveals Mitochondrial Stress as a Central Biological Hub for Spaceflight Impact.

Spaceflight is known to impose changes on human physiology with unknown molecular etiologies. To reveal these causes, we used a multi-omics, systems biology analytical approach using biomedical profiles from fifty-nine astronauts and data from NASA's GeneLab derived from hundreds of samples flown in space to determine transcriptomic, proteomic, metabolomic, and epigenetic responses to spaceflight. Overall pathway analyses on the multi-omics datasets showed significant enrichment for mitochondrial processes, as well as innate immunity, chronic inflammation, cell cycle, circadian rhythm, and olfactory functions. Importantly, NASA's Twin Study provided a platform to confirm several of our principal findings. Evidence of altered mitochondrial function and DNA damage was also found in the urine and blood metabolic data compiled from the astronaut cohort and NASA Twin Study data, indicating mitochondrial stress as a consistent phenotype of spaceflight.

Multi-System-Level Analysis Reveals Differential Expression of Stress Response-Associated Genes in Inflammatory Solar Lentigo.

Although the pathogenesis of solar lentigo (SL) involves chronic ultraviolet (UV) exposure, cellular senescence, and upregulated melanogenesis, underlying molecular-level mechanisms associated with SL remain unclear. The aim of this study was to investigate the gene regulatory mechanisms intimately linked to inflammation in SL. Skin samples from patients with SL with or without histological inflammatory features were obtained. RNA-seq data from the samples were analyzed via multiple analysis approaches, including exploration of core inflammatory gene alterations, identifying functional pathways at both transcription and protein levels, comparison of inflammatory module (gene clusters) activation levels, and analyzing correlations between modules. These analyses disclosed specific core genes implicated in oxidative stress, especially the upregulation of nuclear factor kappa B in the inflammatory SLs, while genes associated with protective mechanisms, such as SLC6A9, were highly expressed in the non-inflammatory SLs. For inflammatory modules, Extracellular Immunity and Mitochondrial Innate Immunity were exclusively upregulated in the inflammatory SL. Analysis of protein-protein interactions revealed the significance of CXCR3 upregulation in the pathogenesis of inflammatory SL. In conclusion, the upregulation of stress response-associated genes and inflammatory pathways in response to UV-induced oxidative stress implies their involvement in the pathogenesis of inflammatory SL.

Multi-System-Level Analysis with RNA-Seq on Pterygium Inflammation Discovers Association between Inflammatory Responses, Oxidative Stress, and Oxidative Phosphorylation.

A pterygium is a common conjunctival degeneration and inflammatory condition. It grows onto the corneal surface or limbus, causing blurred vision and cosmetic issues. Ultraviolet is a well-known risk factor for the development of a pterygium, although its pathogenesis remains unclear, with only limited understanding of its hereditary basis. In this study, we collected RNA-seq from both pterygial tissues and conjunctival tissues (as controls) from six patients (a total of twelve biological samples) and retrieved publicly available data, including eight pterygium samples and eight controls. We investigated the intrinsic gene regulatory mechanisms closely linked to the inflammatory reactions of pterygiums and compared Asian (Korea) and the European (Germany) pterygiums using multiple analysis approaches from different perspectives. The increased expression of antioxidant genes in response to oxidative stress and DNA damage implies an association between these factors and pterygium development. Also, our comparative analysis revealed both similarities and differences between Asian and European pterygiums. The decrease in gene expressions involved in the three primary inflammatory signaling pathways-JAK/STAT, MAPK, and NF-kappa B signaling-suggests a connection between pathway dysfunction and pterygium development. We also observed relatively higher activity of autophagy and antioxidants in the Asian group, while the European group exhibited more pronounced stress responses against oxidative stress. These differences could potentially be necessitated by energy-associated pathways, specifically oxidative phosphorylation.

Expression of AKT1 Related with Clinicopathological Parameters in Clear Cell Renal Cell Carcinoma.

Pathways such as VEGF, EGF and mTOR are known to be one of the major mechanisms of tumorigenesis including kidney cancer. To identify potential signaling pathway proteins, we performed differential/correlation analyses of mTOR-associated genes from three public datasets. AKT1 protein, one of the PI3K/AKT/mTOR pathways, turned out to be the potential by showing a consistent discrepancy between ccRCC-associated conditions as well as strong correlation with other mTOR-associated genes across the datasets. Then, we analyzed how AKT1 alteration affects clear cell renal cell carcinoma. The pathology of 58 kidney cancer patients was constructed to analyze the relationship between the expression level of AKT1 through immunohistochemical staining and their clinicopathological data. Gender, age and TNM stage did not show significant results. AKT1 is a known oncogene. However, in this study, high expression of AKT1 showed a slight correlation with lower WHO/ISUP grade, longer recurrence-free and progression-free survival rates.

Distinct Function of Mediator Subunits in Fungal Development, Stress Response, and Secondary Metabolism in Maize Pathogen Fusarium verticillioides.

Mediator is a nucleus-localized, multisubunit protein complex highly conserved across eukaryotes. It interacts with RNA polymerase II transcription machinery as well as various transcription factors to regulate gene expression. However, systematic characterization of the Mediator complex has not been performed in filamentous fungi. In our study, the goal was to investigate key biological functions of Mediator subunits in a mycotoxigenic plant pathogen Fusarium verticillioides. Although there is some level of divergence in the constituent subunits, the overall structure was conserved between Saccharomyces cerevisiae and F. verticillioides. We generated 11 Mediator subunit deletion mutants and characterized vegetative growth, conidia formation, environmental stress response, carbon and fatty acid use, virulence, and fumonisin B1 (FB1) biosynthesis. Each Mediator subunit deletion mutant showed deficiencies in at least three of the phenotypes tested, suggesting that each subunit has different principal functions in F. verticillioides development, metabolism, and virulence. The deletion of FvMed1 led to increased FB1 production, and we confirmed that FvMed1 is transported from the nucleus to the cytoplasm under fumonisin-producing conditions. Taken together, our study characterized various important functional roles for Mediator subunits in F. verticillioides and suggests that select subunits can perform unique cytoplasmic functions independent of the core Mediator in fungal nucleus.

Scedar: A scalable Python package for single-cell RNA-seq exploratory data analysis.

In single-cell RNA-seq (scRNA-seq) experiments, the number of individual cells has increased exponentially, and the sequencing depth of each cell has decreased significantly. As a result, analyzing scRNA-seq data requires extensive considerations of program efficiency and method selection. In order to reduce the complexity of scRNA-seq data analysis, we present scedar, a scalable Python package for scRNA-seq exploratory data analysis. The package provides a convenient and reliable interface for performing visualization, imputation of gene dropouts, detection of rare transcriptomic profiles, and clustering on large-scale scRNA-seq datasets. The analytical methods are efficient, and they also do not assume that the data follow certain statistical distributions. The package is extensible and modular, which would facilitate the further development of functionalities for future requirements with the open-source development community. The scedar package is distributed under the terms of the MIT license at https://pypi.org/project/scedar.

Comparison of Anterior-Stabilized and Posterior-Stabilized Total Knee Arthroplasty in the Same Patients: A Prospective Randomized Study.

BACKGROUND: A highly conforming, anterior-stabilized (AS) insert is designed to provide anteroposterior (AP) stability of the posterior-stabilized (PS) insert without a post. The purpose of this study was to compare the static and dynamic stability and function of AS and PS total knee arthroplasty (TKA) in the same patients. METHODS: A prospective, randomized controlled trial was performed in 45 patients scheduled to undergo same-day bilateral TKA. One knee was randomly assigned to receive an AS TKA, and the other knee was scheduled for a PS TKA from the same knee system. At 2 years postoperatively, the static AP stability was compared using anterior and posterior drawer stress radiographs at 90° knee flexion. Dynamic AP stability was evaluated using one-leg standing lateral fluoroscopic images throughout the range of motion. Knee function was compared using the Knee Society Score and Western Ontario and McMaster Universities Osteoarthritis Index score. RESULTS: At 2 years postoperatively, there was a significant difference in knee AP laxity at 90° of flexion between the two groups (7.6 ± 3.9 mm in the AS group vs 2.2 ± 2.3 in the PS group, P < .001). However, there were no differences in dynamic AP stability under one-leg standing fluoroscopic lateral images at 30°, 60°, and 90° knee flexion (P = .732, P = .764, and P = .679, respectively). The Knee Society Score and Western Ontario and McMaster Universities Osteoarthritis Index scores were not significantly different between the two groups (P = .641 and P = .582, respectively). CONCLUSION: Despite the fact that the AS TKA group showed significantly more static posterior displacement than the PS TKA group at 90° of knee flexion, both the AS and PS TKA groups showed similar dynamic stability under weight-bearing conditions and knee function at 2 years postoperatively.

Central Sensitization Is a Risk Factor for Persistent Postoperative Pain and Dissatisfaction in Patients Undergoing Revision Total Knee Arthroplasty.

BACKGROUND: The objective of this study is to investigate whether central sensitization (CS) was associated with patient dissatisfaction after revision total knee arthroplasty (TKA). METHODS: Between 2012 and 2016, 68 cases (68 patients) of revision TKA performed by a single surgeon were included in this study with a minimum follow-up of 2 years. Patients were categorized into 2 groups by 40-point preoperative Central Sensitization Inventory (CSI) scores. The control group consisted of 48 patients (48 knees) with CSI scores of less than 40 points, while the CS group consisted of 20 patients (20 knees) with CSI scores of 40 points or more. Clinical outcomes were evaluated using an 11-point visual analog scale (VAS) and Western Ontario and McMaster Universities Osteoarthritis Index scores. Patient satisfaction was evaluated using the satisfaction items of the new Knee Society Scores, where scores ≥20 indicated satisfaction. RESULTS: Higher preoperative pain VAS scores in the CS group were maintained 3, 6, 12, and 24 months postoperatively (all P < .05). The CS group showed significantly worse pain, function subscores, and total scores of the Western Ontario and McMaster Universities Osteoarthritis Index preoperatively and at 2 years postoperatively. Forty-four (91.7%) patients in the control group and 3 (15.0%) patients in the CS group were satisfied with their revision TKAs (P < .001). Multivariate logistic regression analysis demonstrated that the odds of dissatisfaction after revision TKAs were increased 39.081 times (95% confidence interval 6.926-220.504, P < .001) in patients with CSI scores ≥40. Higher VAS intensity 2 years postoperatively also predicted dissatisfaction following revision TKA (odds ratio 1.864, 95% confidence interval 1.086-3.199, P = .024). CONCLUSION: CS is a risk factor for persistent postoperative pain and dissatisfaction in patients undergoing revision TKAs. LEVEL OF EVIDENCE: III.

Autologous Impaction Bone Grafting for Bone Defects of the Medial Tibia Plateau During Primary Total Knee Arthroplasty: Propensity Score Matched Analysis With a Minimum of 7-Year Follow-Up.

BACKGROUND: The aims of this study were to (1) describe a novel technique for appropriate treatment of bone defects in medial tibial plateau grafted with autologous resected bone and (2) compare clinical outcomes, radiographic results, and survivorship of these knees with those of standard total knee arthroplasty (TKA) without bone defect. METHODS: We retrospectively reviewed 50 cases of primary TKA involving bone defects of medial tibial plateau managed with bone grafting for a minimum follow-up of 7 years. Autologous resected bones were used for bone graft after removing solid cortical bones at the defect site. After bone graft group was completed, one-to-one patient-matched control was accomplished based on propensity score matching of 50 knees. Survivorship was analyzed using the Kaplan-Meier method. The endpoint of survival was revision of implant. Clinical outcomes were also assessed including Knee Society Score and Western Ontario and McMaster Universities Osteoarthritis Index score. RESULTS: The mean follow-up was 117 months in the group with bone graft and 108 months in the group without bone graft. There were no significant differences in postoperative clinical scores and knee alignment. Nonprogressive radiolucent lines measuring <2 mm were observed in 8 knees in the group with bone graft and 9 knees in the group without bone graft. During the follow-up period, 1 patient with late infection underwent 2-stage revision and another revision for tibial loosening occurred in both groups. The 10-year cumulative survival rate for revision was 96.0% in both groups. CONCLUSION: Our technique of management of medial tibial bone defect using autologous bone graft yielded desirable results based on survival rate and clinical outcome.

Differences in Patient-Reported Outcomes Between Unicompartmental and Total Knee Arthroplasties: A Propensity Score-Matched Analysis.

BACKGROUND: The purpose of this study was to compare the patient-reported outcomes regarding joint awareness, function, and satisfaction after unicompartmental knee arthroplasty (UKA) and total knee arthroplasty (TKA). METHODS: We identified all patients who underwent a UKA or TKA at our institution between September 2011 and March 2014, with a minimum follow-up of 2 years. Propensity score matching was performed for age, gender, body mass index, operation side, and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score. One hundred UKAs to 100 TKAs were matched. Each knee was evaluated according to the WOMAC score, Forgotten Joint Score (FJS), High Flexion Knee Score (HFKS) and patient's satisfaction at postoperative 2 years. RESULTS: There was no significant difference in WOMAC score at postoperative 2 years between UKA and TKA groups. However, the FJS of the UKA group was significantly higher than that of the TKA group (67.3 ± 19.8 and 60.6 ± 16.6, respectively; P = .011). The HFKS was also significantly higher in the UKA group compared with the TKA group (34.4 ± 6.4 and 31.3 ± 5.2, respectively; P < .001). Eighty-six percent of all patients who underwent UKA were satisfied compared with 71% of those who underwent TKA (P = .027). CONCLUSION: Patients who underwent UKA had higher FJS, HFKS, and satisfaction rate when compared with patients who underwent TKA, indicating that UKA facilitated less knee awareness and better function and satisfaction than TKA.

Correcting Severe Varus Deformity Using Trial Components During Total Knee Arthroplasty.

BACKGROUND: Extensive medial soft tissue release may be necessary to correct severe varus deformity during total knee arthroplasty (TKA). However, this procedure may result in instability. Here, we describe a novel soft tissue balancing technique, which can minimize medial release in severe varus deformity during TKA. METHODS: Fifty knees (40 patients) with hip-knee-ankle angle of more than 20° of varus were corrected using this technique (group 1). After achieving flexion gap balancing by needle puncturing and spreading of the superficial medial collateral ligament, extension gap balancing was obtained by gradual extension with the trial components in place. After group 1 was set, a one-to-one patient-matched control group who had mild varus deformity was selected by propensity score matching (50 knees, 48 patients, group 2). At postoperative 1 year, mediolateral laxity was compared between the 2 groups using the stress radiographs. Clinical outcomes were also compared using the Knee Society Score and Western Ontario and McMaster Universities Osteoarthritis Index score. RESULTS: There were no differences in mean medial and lateral laxities between groups 1 and 2 at 1 year after the operation (medial laxity: 2.3° ± 1.4° and 2.7° ± 1.3°, respectively, P = .310) (lateral laxity: 3.6° ± 1.7° and 3.2° ± 2.0°, respectively, P = .459). There were no significant differences in postoperative clinical scores and knee alignment. CONCLUSION: Our technique of obtaining extension gap balancing using trial components led to safe and effective balancing by avoiding unnecessary extensive release in severe varus deformity during TKA.

Does Patient Perception Differ Following Adductor Canal Block and Femoral Nerve Block in Total Knee Arthroplasty? A Simultaneous Bilateral Randomized Study.

BACKGROUND: Femoral nerve block (FNB) has been used as part of the multimodal analgesia after total knee arthroplasty (TKA), but leads to weakness in the quadriceps muscles. Recently, adductor canal block (ACB) was reported to provide effective pain relief while sparing the strength of the quadriceps. This simultaneous bilateral randomized study investigated whether patients perceived differences between ACB and the FNB after same-day bilateral TKA. METHODS: We performed a prospective simultaneous bilateral randomized study in 50 patients scheduled to undergo same-day bilateral TKA. One knee was randomly assigned to ACB and the other knee was assigned to FNB. All ACB and FNB were performed using ultrasound-guided single-shot procedures. These 2 groups were compared for pain visual analogue scale, straight leg raising ability and knee extension while sitting, and motor grade. At postoperative week 1, the peak torque for the quadriceps muscle was measured in both knees with an isokinetic dynamometer. RESULTS: There were no differences in pain levels between ACB and FNB during the entire study period. During the first 48 h after TKA, more of the knees that received ACB could perform straight leg raising and knee extension with greater quadriceps strength compared with FNB. However, no group differences in quadriceps functional recovery were found after postoperative 48 h and isometric quadriceps strength at postoperative 1 week. CONCLUSION: This simultaneous bilateral randomized study demonstrates that patients did not perceive differences in pain level, but experienced substantial differences in quadriceps strength recovery between knees during the first 48 h (Identifier: NCT02513082).

Guarea microcarpa C. DC. extract inhibits NLRP3 inflammasome by suppressing its ATPase activity.

ETHNOPHARMACOLOGICAL RELEVANCE: Guarea genus comprises tropical and subtropical terrestrial herbs inhabiting Central and South America. These plants, including Guarea guidonia (L.) Sleumer, have anti-inflammatory, analgesic, antibacterial, antiviral, and immune-enhancing properties. AIM OF THE STUDY: Although various species of the Guarea genus are known for their medicinal properties, comprehensive data on their anti-inflammatory effects remain limited. Therefore, we investigated the NLRP3 inflammasome-inhibiting effects of the Guarea genus in this study. MATERIALS AND METHODS: To evaluate the anti-inflammatory activities of 18 members of the Guarea genus, we treated NLRP3 inflammasome activators with their extracts in LPS-primed J774A.1 and THP-1 cells. Cell viability was determined by water soluble tetrazolium salt (WST) and cytokine production, protein expression, and nuclear fractionation were determined by western blotting. Reactive oxygen species (ROS) production and apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) oligomerization were measured using confocal microscopic analysis. Inflammation-induced zebrafish was used in the in vivo experiments. RESULTS: Among the 18 Guarea members tested, Guarea microcarpa C. DC. extract (GM) exhibited no cytotoxicity and specifically suppressed the activation of the NLRP3 inflammasome, but not of the AIM2 or NLRC4 inflammasomes, by inhibiting the ATPase activity of NLRP3. This was achieved without affecting NF-κB signaling, potassium efflux, or intracellular ROS production, all of which are involved in NLRP3 activation. The reduced ATPase activity of NLRP3 led to decreased ASC oligomerization. Furthermore, GM exhibited anti-inflammatory effects in vivo. Additionally, GM treatment alleviated inflammation at the organismal level in an LPS-induced inflammation model using zebrafish embryos. CONCLUSION: Our results demonstrate the anti-inflammatory effects of GM via suppressing the NLRP3 inflammasome. Therefore, GM can be a potential therapeutic candidate for various inflammatory diseases caused by aberrant NLRP3 inflammasome activation.

Aiouea padiformis extract exhibits anti-inflammatory effects by inhibiting the ATPase activity of NLRP3.

Inflammation is implicated as a cause in many diseases. Most of the anti-inflammatory agents in use are synthetic and there is an unmet need for natural substance-derived anti-inflammatory agents with minimal side effects. Aiouea padiformis belongs to the Lauraceae family and is primarily found in tropical regions. While some members of the Aiouea genus are known to possess anti-inflammatory properties, the anti-inflammatory properties of Aiouea padiformis extract (AP) have not been investigated. In this study, we aimed to examine the anti-inflammatory function of AP through the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome and elucidate the underlying mechanisms. Treatment with AP inhibited the secretion of interleukin-1 beta (IL-1ß) mediated by NLRP3 inflammasome in J774A.1 and THP-1 cells without affecting the viability. In addition, AP treatment did not influence NF-κB signaling, potassium efflux, or intracellular reactive oxygen species (ROS) production-all of which are associated with NLRP3 inflammasome activation. However, intriguingly, AP treatment significantly reduced the ATPase activity of NLRP3, leading to the inhibition of ASC oligomerization and speck formation. Consistent with cellular experiments, the anti-inflammatory property of AP in vivo was also evaluated using an LPS-induced inflammation model in zebrafish, demonstrating that AP hinders NLRP3 inflammasome activation.

RNA-Seq of an LPS-Induced Inflammation Model Reveals Transcriptional Profile Patterns of Inflammatory Processes.

The LPS-induced inflammation model is widely used for studying inflammatory processes due to its cost-effectiveness, reproducibility, and faithful representation of key hallmarks. While researchers often validate this model using clinical cytokine markers, a comprehensive understanding of gene regulatory mechanisms requires extending investigation beyond these hallmarks. Our study leveraged multiple whole-blood bulk RNA-seq datasets to rigorously compare the transcriptional profiles of the well-established LPS-induced inflammation model with those of several human diseases characterized by systemic inflammation. Beyond conventional inflammation-associated systems, we explored additional systems indirectly associated with inflammatory responses (i.e., ISR, RAAS, and UPR) using a customized core inflammatory gene list. Our cross-condition-validation approach spanned four distinct conditions: systemic lupus erythematosus (SLE) patients, dengue infection, candidemia infection, and staphylococcus aureus exposure. This analysis approach, utilizing the core gene list aimed to assess the model's suitability for understanding the gene regulatory mechanisms underlying inflammatory processes triggered by diverse factors. Our analysis resulted in elevated expressions of innate immune-associated genes, coinciding with suppressed expressions of adaptive immune-associated genes. Also, upregulation of genes associated with cellular stresses and mitochondrial innate immune responses underscored oxidative stress as a central driver of the corresponding inflammatory processes in both the LPS-induced and other inflammatory contexts.

Maternal PM2.5 exposure is associated with preterm birth and gestational diabetes mellitus, and mitochondrial OXPHOS dysfunction in cord blood.

Maternal exposure to fine particulate matter (PM2.5) is associated with adverse pregnancy and neonatal health outcomes. To explore the mechanism, we performed mRNA sequencing of neonatal cord blood. From an ongoing prospective cohort, Air Pollution on Pregnancy Outcome (APPO) study, 454 pregnant women from six centers between January 2021 and June 2022 were recruited. Individual PM2.5 exposure was calculated using a time-weighted average model. In the APPO study, age-matched cord blood samples from the High PM2.5 (˃15 ug/m3; n = 10) and Low PM2.5 (≤ 15 ug/m3; n = 30) groups were randomly selected for mRNA sequencing. After selecting genes with differential expression in the two groups (p-value < 0.05 and log2 fold change > 1.5), pathway enrichment analysis was performed, and the mitochondrial pathway was analyzed using MitoCarta3.0. The risk of preterm birth (PTB) increased with every 5 µg/m3 increase of PM2.5 in the second trimester (odds ratio 1.391, p = 0.019) after adjusting for confounding variables. The risk of gestational diabetes mellitus (GDM) increased in the second (odds ratio 1.238, p = 0.041) and third trimester (odds ratio 1.290, p = 0.029), and entire pregnancy (odds ratio 1.295, p = 0.029). The mRNA-sequencing of cord blood showed that genes related to mitochondrial activity (FAM210B, KRT1, FOXO4, TRIM58, and FBXO7) and PTB-related genes (ADIPOR1, YBX1, OPTN, NFkB1, HBG2) were upregulated in the High PM2.5 group. In addition, exposure to high PM2.5 affected mitochondrial oxidative phosphorylation (OXPHOS) and proteins in the electron transport chain, a subunit of OXPHOS. These results suggest that exposure to high PM2.5 during pregnancy may increase the risk of PTB and GDM, and dysregulate PTB-related genes. Alterations in mitochondrial OXPHOS by high PM2.5 exposure may occur not only in preterm infants but also in normal newborns. Further studies with larger sample sizes are required.

Aging and putative frailty biomarkers are altered by spaceflight.

Human space exploration poses inherent risks to astronauts' health, leading to molecular changes that can significantly impact their well-being. These alterations encompass genomic instability, mitochondrial dysfunction, increased inflammation, homeostatic dysregulation, and various epigenomic changes. Remarkably, these changes bear similarities to those observed during the aging process on Earth. However, our understanding of the connection between these molecular shifts and disease development in space remains limited. Frailty syndrome, a clinical syndrome associated with biological aging, has not been comprehensively investigated during spaceflight. To bridge this knowledge gap, we leveraged murine data obtained from NASA's GeneLab, along with astronaut data gathered from the JAXA and Inspiration4 missions. Our objective was to assess the presence of biological markers and pathways related to frailty, aging, and sarcopenia within the spaceflight context. Through our analysis, we identified notable changes in gene expression patterns that may be indicative of the development of a frailty-like condition during space missions. These findings suggest that the parallels between spaceflight and the aging process may extend to encompass frailty as well. Consequently, further investigations exploring the utility of a frailty index in monitoring astronaut health appear to be warranted.

Geographic Variations and the Associated Factors in Adherence to and Persistence with Adjuvant Hormonal Therapy for the Privately Insured women Aged 18-64 with Breast Cancer in Texas.

The purpose of this study is to examine the geographical patterns of adjuvant hormonal therapy adherence and persistence and the associated factors in insured Texan women aged 18-64 with early breast cancer. A retrospective cohort study was conducted using 5-year claims data for the population insured by the Blue Cross Blue Shield of Texas (BCBSTX). Women diagnosed with early breast cancer who were taking tamoxifen or aromatase inhibitors (AIs) for adjuvant hormonal therapy with at least one prescription claim were identified. Adherence to adjuvant hormonal therapy and persistence with adjuvant hormonal therapy were calculated as outcome measures. Women without a gap between two consecutively dispensed prescriptions of at least 90 days were considered to be persistently taking the medications. Patient-level multivariate logistic regression models with repeated regional-level adjustments and a Cox proportional hazards model with mixed effects were used to determine the geographical variations and patient-, provider-, and area-level factors that were associated with adjuvant hormonal therapy adherence and persistence. Of the 938 women in the cohort, 627 (66.8%) initiated adjuvant hormonal therapy. Most of the smaller HRRs have significantly higher or lower rates of treatment adherence and persistence rates relative to the median regions. The use of AHT varies substantially from one geographical area to another, especially for adherence, with an approximately two-fold difference between the lowest and highest areas, and area-level factors were found to be significantly associated with the compliance of AHT. There are geographical variations in AHT adherence and persistence in Texas. Patient-level and area-level factors have significant associations explaining these patterns.

PTEN-induced kinase 1 is associated with renal aging, via the cGAS-STING pathway.

Mitochondrial dysfunction is considered to be an important mediator of the pro-aging process in chronic kidney disease, which is continuously increasing worldwide. Although PTEN-induced kinase 1 (PINK1) regulates mitochondrial function, its role in renal aging remains unclear. We investigated the association between PINK1 and renal aging, especially through the cGAS-STING pathway, which is known to result in an inflammatory phenotype. Pink1 knockout (Pink1-/- ) C57BL/6 mice and senescence-induced renal tubular epithelial cells (HKC-8) treated with H2 O2 were used as the renal aging models. Extensive analyses at transcriptomic-metabolic levels have explored changes in mitochondrial function in PINK1 deficiency. To investigate whether PINK1 deficiency affects renal aging through the cGAS-STING pathway, we explored their expression levels in PINK1 knockout mice and senescence-induced HKC-8 cells. PINK1 deficiency enhances kidney fibrosis and tubular injury, and increases senescence and the senescence-associated secretory phenotype (SASP). These phenomena were most apparent in the 24-month-old Pink1-/- mice and HKC-8 cells treated with PINK1 siRNA and H2 O2 . Gene expression analysis using RNA sequencing showed that PINK1 deficiency is associated with increased inflammatory responses, and transcriptomic and metabolomic analyses suggested that PINK1 deficiency is related to mitochondrial metabolic dysregulation. Activation of cGAS-STING was prominent in the 24-month-old Pink1-/- mice. The expression of SASPs was most noticeable in senescence-induced HKC-8 cells and was attenuated by the STING inhibitor, H151. PINK1 is associated with renal aging, and mitochondrial dysregulation by PINK1 deficiency might stimulate the cGAS-STING pathway, eventually leading to senescence-related inflammatory responses.

RNA-Sequencing Analysis Reveals the Role of Mitochondrial Energy Metabolism Alterations and Immune Cell Activation in Form-Deprivation and Lens-Induced Myopia in Mice.

Myopia is a substantial global public health concern primarily linked to the elongation of the axial length of the eyeball. While numerous animal models have been employed to investigate myopia, the specific contributions of genetic factors and the intricate signaling pathways involved remain incompletely understood. In this study, we conducted RNA-seq analysis to explore genes and pathways in two distinct myopia-inducing mouse models: form-deprivation myopia (FDM) and lens-induced myopia (LIM). Comparative analysis with a control group revealed significant differential expression of 2362 genes in FDM and 503 genes in LIM. Gene Set Enrichment Analysis (GSEA) identified a common immune-associated pathway between LIM and FDM, with LIM exhibiting more extensive interactions. Notably, downregulation was observed in OxPhos complex III of FDM and complex IV of LIM. Subunit A of complex I was downregulated in LIM but upregulated in FDM. Additionally, complex V was upregulated in LIM but downregulated in FDM. These findings suggest a connection between alterations in energy metabolism and immune cell activation, shedding light on a novel avenue for understanding myopia's pathophysiology. Our research underscores the necessity for a comprehensive approach to comprehending myopia development, which integrates insights from energy metabolism, oxidative stress, and immune response pathways.