Investigating Heterogeneous Cell-Cycle Progression Using Single-Cell Imaging Approaches.

Investigating cell-cycle progression has been challenging due to the complex interconnectivity of regulatory processes and inherent cell-to-cell heterogeneity, which often require synchronization procedures. However, recent advancements in cell-cycle sensors and single-cell imaging techniques have turned this heterogeneity into an advantage for investigating the molecular mechanisms underlying diverse responses. This has led to significant progress in our understanding of cell-cycle regulation. In this paper, we present a comprehensive live single-cell imaging workflow that leverages cutting-edge live-cell sensors. These advanced single-cell imaging procedures provide promising opportunities for elucidating the molecular mechanisms underpinnings of heterogeneous responses in cell-cycle progression.

Non-canonical pathway for Rb inactivation and external signaling coordinate cell-cycle entry without CDK4/6 activity.

Cyclin-dependent kinases 4 and 6 (CDK4/6) are critical for initiating cell proliferation by inactivating the retinoblastoma (Rb) protein. However, mammalian cells can bypass CDK4/6 for Rb inactivation. Here we show a non-canonical pathway for Rb inactivation and its interplay with external signals. We find that the non-phosphorylated Rb protein in quiescent cells is intrinsically unstable, offering an alternative mechanism for initiating E2F activity. Nevertheless, this pathway incompletely induces Rb-protein loss, resulting in minimal E2F activity. To trigger cell proliferation, upregulation of mitogenic signaling is required for stabilizing c-Myc, thereby augmenting E2F activity. Concurrently, stress signaling promotes Cip/Kip levels, competitively regulating cell proliferation with mitogenic signaling. In cancer, driver mutations elevate c-Myc levels, facilitating adaptation to CDK4/6 inhibitors. Differentiated cells, despite Rb-protein loss, maintain quiescence through the modulation of c-Myc and Cip/Kip levels. Our findings provide mechanistic insights into an alternative model of cell-cycle entry and the maintenance of quiescence.

What is the impact of one's chronic illness on his or her spouse's future chronic illness: a community-based prospective cohort study.

BACKGROUND: Integrating a joint approach to chronic disease management within the context of a couple has immense potential as a valuable strategy for both prevention and treatment. Although spousal concordance has been reported in specific chronic illnesses, the impact they cumulatively exert on a spouse in a longitudinal setting has not been investigated. We aimed to determine whether one's cumulative illness burden has a longitudinal impact on that of their spouse. METHODS: Data was acquired from a community-based prospective cohort that included Koreans aged 60 years and over, randomly sampled from 13 districts nationwide. Data from the baseline assessment (conducted from November 2010 to October 2012) up to the 8-year follow-up assessment was analyzed from October 2021 to November 2022. At the last assessment, partners of the index participants were invited, and we included 814 couples in the analysis after excluding 51 with incomplete variables. Chronic illness burden of the participants was measured by the Cumulative Illness Rating Scale (CIRS). Multivariable linear regression and causal mediation analysis were used to examine the longitudinal effects of index chronic illness burden at baseline and its change during follow-up on future index and spouse CIRS scores. RESULTS: Index participants were divided based on baseline CIRS scores (CIRS < 6 points, n = 555, mean [SD] age 66.3 [4.79] years, 43% women; CIRS ≥ 6 points, n = 259, mean [SD] age 67.7 [4.76] years, 36% women). The baseline index CIRS scores and change in index CIRS scores during follow-up were associated with the spouse CIRS scores (ß = 0.154 [SE: 0.039], p < 0.001 for baseline index CIRS; ß = 0.126 [SE: 0.041], p = 0.002 for change in index CIRS) at the 8-year follow-up assessment. Subgroup analysis found similar results only in the high CIRS group. The baseline index CIRS scores and change in index CIRS scores during follow-up had both direct and indirect effects on the spouse CIRS scores at the 8-year follow-up assessment. CONCLUSIONS: The severity and course of one's chronic illnesses had a significant effect on their spouse's future chronic illness particularly when it was severe. Management strategies for chronic diseases that are centered on couples may be more effective.

Angiopoietin-2 blockade suppresses growth of liver metastases from pancreatic neuroendocrine tumors by promoting T cell recruitment.

Improving the management of metastasis in pancreatic neuroendocrine tumors (PanNETs) is critical, as nearly half of patients with PanNETs present with liver metastases, and this accounts for the majority of patient mortality. We identified angiopoietin-2 (ANGPT2) as one of the most upregulated angiogenic factors in RNA-Seq data from human PanNET liver metastases and found that higher ANGPT2 expression correlated with poor survival rates. Immunohistochemical staining revealed that ANGPT2 was localized to the endothelial cells of blood vessels in PanNET liver metastases. We observed an association between the upregulation of endothelial ANGPT2 and liver metastatic progression in both patients and transgenic mouse models of PanNETs. In human and mouse PanNET liver metastases, ANGPT2 upregulation coincided with poor T cell infiltration, indicative of an immunosuppressive tumor microenvironment. Notably, both pharmacologic inhibition and genetic deletion of ANGPT2 in PanNET mouse models slowed the growth of PanNET liver metastases. Furthermore, pharmacologic inhibition of ANGPT2 promoted T cell infiltration and activation in liver metastases, improving the survival of mice with metastatic PanNETs. These changes were accompanied by reduced plasma leakage and improved vascular integrity in metastases. Together, these findings suggest that ANGPT2 blockade may be an effective strategy for promoting T cell infiltration and immunostimulatory reprogramming to reduce the growth of liver metastases in PanNETs.

Sequential activation of E2F via Rb degradation and c-Myc drives resistance to CDK4/6 inhibitors in breast cancer.

Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) are key therapeutic agents in the management of metastatic hormone-receptor-positive breast cancer. However, the emergence of drug resistance limits their long-term efficacy. Here, we show that breast cancer cells develop CDK4/6i resistance via a sequential two-step process of E2F activation. This process entails retinoblastoma (Rb)-protein degradation, followed by c-Myc-mediated amplification of E2F transcriptional activity. CDK4/6i treatment halts cell proliferation in an Rb-dependent manner but dramatically reduces Rb-protein levels. However, this reduction in Rb levels insufficiently induces E2F activity. To develop CDK4/6i resistance, upregulation or activating mutations in mitogenic or hormone signaling are required to stabilize c-Myc levels, thereby augmenting E2F activity. Our analysis of pre-treatment tumor samples reveals a strong correlation between c-Myc levels, rather than Rb levels, and poor therapeutic outcomes after CDK4/6i treatment. Moreover, we propose that proteasome inhibitors can potentially reverse CDK4/6i resistance by restoring Rb levels.

The impact of the COVID-19 pandemic on depression in community-dwelling older adults: a prospective cohort study.

BACKGROUND: There are growing concerns about the impact of the COVID-19 pandemic on the mental health of older adults. We examined the effect of the pandemic on the risk of depression in older adults. METHODS: We analyzed data from the prospective cohort study of Korean older adults, which has been followed every 2 years. Among the 2308 participants who completed both the third and the fourth follow-up assessments, 58.4% completed their fourth follow-up before the outbreak of COVID-19 and the rest completed it during the pandemic. We conducted face-to-face diagnostic interviews using Mini International Neuropsychiatric Interview and used Geriatric Depression Scale. We performed generalized estimating equations and logistic regression analyses. RESULTS: The COVID-19 pandemic was associated with increased depressive symptoms in older adults [b (standard error) = 0.42 (0.20), p = 0.040] and a doubling of the risk for incident depressive disorder even in euthymic older adults without a history of depression (odds ratio = 2.44, 95% confidence interval 1.18-5.02, p = 0.016). Less social activities, which was associated with the risk of depressive disorder before the pandemic, was not associated with the risk of depressive disorder during the pandemic. However, less family gatherings, which was not associated with the risk of depressive disorder before the pandemic, was associated with the doubled risk of depressive disorder during the pandemic. CONCLUSIONS: The COVID-19 pandemic significantly influences the risk of late-life depression in the community. Older adults with a lack of family gatherings may be particularly vulnerable.

Kinetics of RTK activation determine ERK reactivation and resistance to dual BRAF/MEK inhibition in melanoma.

The combination of BRAF and MEK inhibitors (BRAFi/MEKi) has shown promising response rates in treating BRAF-mutant melanoma by inhibiting ERK activation. However, treatment efficacy is limited by the emergence of drug-tolerant persister cells (persisters). Here, we show that the magnitude and duration of receptor tyrosine kinase (RTK) activation determine ERK reactivation and persister development. Our single-cell analysis reveals that only a small subset of melanoma cells exhibits effective RTK and ERK activation and develops persisters, despite uniform external stimuli. The kinetics of RTK activation directly influence ERK signaling dynamics and persister development. These initially rare persisters form major resistant clones through effective RTK-mediated ERK activation. Consequently, limiting RTK signaling suppresses ERK activation and cell proliferation in drug-resistant cells. Our findings provide non-genetic mechanistic insights into the role of heterogeneity in RTK activation kinetics in ERK reactivation and BRAFi/MEKi resistance, suggesting potential strategies for overcoming drug resistance in BRAF-mutant melanoma.

A normative study of the gait features measured by a wearable inertia sensor in a healthy old population.

BACKGROUND: Gait function impairments are associated with the risk of various medical conditions in older adults. As gait function declines with advancing age, normative data are required for proper interpretation of gait function in older adults. RESEARCH PURPOSE: This study aimed to construct age-stratified normative data of non-dimensionally normalized temporal and spatial gait features in healthy older adults. METHODS: We recruited 320 community-dwelling healthy adults aged 65 years or older from two prospective cohort studies. We stratified them into four age groups (65-69, 70-74, 75-79, and 80-84 years). Each age group comprised 40 men and 40 women. We obtained six gait features (cadence, step time, step time variability, step time asymmetry, gait speed, and step length) using a wearable inertia measurement unit attached on the skin overlying L3-L4 on the back. To mitigate the influence of body shape, we non-dimensionally normalized the gait features into unitless values using height and gravity. RESULT: The effect of age group was significant in all raw gait features (p < 0.001 for step time variability, speed and step length; p < 0.05 for cadence, step time and step time asymmetry), and that of sex was significant in the five raw gait features, except for step time asymmetry(p < 0.001 for cadence, step time, speed, and step length; p < 0.05 for step time asymmetry). When gait features were normalized, the effect of age group remained (p < 0.001 for all gait features), whereas that of sex disappeared (p > 0.05 for all gait features). SIGNIFICANCE: Our dimensionless normative data on gait features may be useful in comparative studies of gait function between sexes or ethnicities with different body shapes.

Angiopoietin-2-Dependent Spatial Vascular Destabilization Promotes T-cell Exclusion and Limits Immunotherapy in Melanoma.

T-cell position in the tumor microenvironment determines the probability of target encounter and tumor killing. CD8+ T-cell exclusion from the tumor parenchyma is associated with poor response to immunotherapy, and yet the biology that underpins this distinct pattern remains unclear. Here we show that the vascular destabilizing factor angiopoietin-2 (ANGPT2) causes compromised vascular integrity in the tumor periphery, leading to impaired T-cell infiltration to the tumor core. The spatial regulation of ANGPT2 in whole tumor cross-sections was analyzed in conjunction with T-cell distribution, vascular integrity, and response to immunotherapy in syngeneic murine melanoma models. T-cell exclusion was associated with ANGPT2 upregulation and elevated vascular leakage at the periphery of human and murine melanomas. Both pharmacologic and genetic blockade of ANGPT2 promoted CD8+ T-cell infiltration into the tumor core, exerting antitumor effects. Importantly, the reversal of T-cell exclusion following ANGPT2 blockade not only enhanced response to anti-PD-1 immune checkpoint blockade therapy in immunogenic, therapy-responsive mouse melanomas, but it also rendered nonresponsive tumors susceptible to immunotherapy. Therapeutic response after ANGPT2 blockade, driven by improved CD8+ T-cell infiltration to the tumor core, coincided with spatial TIE2 signaling activation and increased vascular integrity at the tumor periphery where endothelial expression of adhesion molecules was reduced. These data highlight ANGPT2/TIE2 signaling as a key mediator of T-cell exclusion and a promising target to potentiate immune checkpoint blockade efficacy in melanoma. SIGNIFICANCE: ANGPT2 limits the efficacy of immunotherapy by inducing vascular destabilization at the tumor periphery to promote T-cell exclusion.

Shared Risk Factors for Depressive Disorder Among Older Adult Couples in Korea.

Importance: Although couples may share many risk factors for depressive disorders in their lifetime, whether these factors mediate the shared risk of depressive disorders has rarely been investigated. Objectives: To identify the shared risk factors for depressive disorder in couples and investigate their mediating roles in the shared risk of depressive disorders among older adult couples. Design, Setting, and Participants: This nationwide, multicenter, community-based cohort study assessed 956 older adults from the Korean Longitudinal Study on Cognitive Aging and Dementia (KLOSCAD) and a cohort of their spouses (KLOSCAD-S) between January 1, 2019, to February 28, 2021. Exposures: Depressive disorders of the KLOSCAD participants. Main Outcomes and Measures: The mediating roles of shared factors in couples on the association between one spouse's depressive disorder and the other's risk of depressive disorders was examined using structural equation modeling. Results: A total of 956 KLOSCAD participants (385 women [40.3%] and 571 men [59.7%]; mean [SD] age, 75.1 [5.0] years) and their spouses (571 women [59.7%] and 385 men [40.3%]; mean [SD] age, 73.9 [6.1] years) were included. The depressive disorders of the KLOSCAD participants were associated with an almost 4-fold higher risk of depressive disorders in their spouses in the KLOSCAD-S cohort (odds ratio, 3.89; 95% CI, 2.06-7.19; P < .001). Social-emotional support mediated the association between depressive disorders in the KLOSCAD participants and their spouses' risk of depressive disorders by itself (ß = 0.012; 95% CI, 0.001-0.024; P = .04; mediation proportion [MP] = 6.1%) and through chronic illness burden (ß = 0.003; 95% CI, 0.000-0.006; P = .04; MP = 1.5%). Chronic medical illness burden (ß = 0.025; 95% CI, 0.001-0.050; P = .04; MP = 12.6%) and presence of a cognitive disorder (ß = 0.027; 95% CI, 0.003-0.051; P = .03; MP = 13.6%) mediated the association. Conclusions and Relevance: The risk factors shared by older adult couples may mediate approximately one-third of the spousal risk of depressive disorders. Identification of and intervention in the shared risk factors of depression among older adult couples may reduce the risk of depressive disorders in the spouses of older adults with depression.

Exploring age-related changes in saccades during cognitive tasks in healthy adults.

Introduction: Although eye movements such as saccades are related to internal cognitive processes and are independent of visual processing, few studies have investigated whether non-visual cognitive tasks simultaneously affect horizontal and vertical saccades in younger and older adults. Methods: We recruited 28 younger adults aged 20-29 years and 26 older adults aged >60 years through advertisements in community settings. All participants were free of major psychiatric, neurological, or ocular diseases. All participants performed the mental arithmetic task (MAT) and verbal fluency task (VFT). The primary measures were saccade parameters, including frequency, mean amplitude, and mean velocity. Results: During MAT and VFT, the frequencies of horizontal and vertical saccades increased (p = 0.0005 for horizontal saccade in MAT; p < 0.0001 for horizontal saccade in VFT; p = 0.012 for vertical saccade in MAT; p = 0.001 for vertical saccade in VFT), but were comparable between MAT and VFT. The old group showed a slower vertical saccade than the young group during the tasks (p = 0.011 in the MAT phase; p = 0.006 in the VFT phase). The amplitude of the horizontal saccade decreased in both groups during MAT compared to the resting period (p = 0.013), but did not change significantly during VFT. Discussion: Saccade parameters can change during non-visual cognitive tasks with differences between age groups and saccade directions. This study significantly contributes to our understanding of the distinct dynamics of horizontal and vertical saccades across various age group in cognitive aging, despite its restricted focus on specific saccade parameters and cognitive tasks, and inclusion solely of cognitively normal individuals. This study highlights the importance of saccade analysis in elucidating age-related cognitive changes. In conclusion, saccades should be examined in future studies as a potential non-invasive biomarker for early detection of cognitive decline and neurodegenerative diseases.

CDK4/6 initiates Rb inactivation and CDK2 activity coordinates cell-cycle commitment and G1/S transition.

External signaling controls cell-cycle entry until cells irreversibly commit to the cell cycle to ensure faithful DNA replication. This process is tightly regulated by cyclin-dependent kinases (CDKs) and the retinoblastoma protein (Rb). Here, using live-cell sensors for CDK4/6 and CDK2 activities, we propose that CDK4/6 initiates Rb inactivation and CDK2 activation, which coordinates the timing of cell-cycle commitment and sequential G1/S transition. Our data show that CDK4/6 activation induces Rb inactivation and thereby E2F activation, driving a gradual increase in CDK2 activity. We found that rapid CDK4/6 inhibition can reverse cell-cycle entry until CDK2 activity reaches to high levels. This suggests that high CDK2 activity is required to initiate CDK2-Rb positive feedback and CDK4/6-indpendent cell-cycle progression. Since CDK2 activation also facilitates initiation of DNA replication, the timing of CDK2-Rb positive feedback is coupled with the G1/S transition. Our experiments, which acutely increased CDK2 activity by cyclin E1 overexpression, indicate that cells commit to the cell cycle before triggering DNA replication. Together, our data suggest that CDK4/6 inactivates Rb to begin E2F and CDK2 activation, and high CDK2 activity is necessary and sufficient to generate a bistable switch for Rb phosphorylation before DNA replication. These findings highlight how cells initiate the cell cycle and subsequently commit to the cell cycle before the G1/S transition.

Deep learning-based diagnosis of Alzheimer's disease using brain magnetic resonance images: an empirical study.

The limited accessibility of medical specialists for Alzheimer's disease (AD) can make obtaining an accurate diagnosis in a timely manner challenging and may influence prognosis. We investigated whether VUNO Med-DeepBrain AD (DBAD) using a deep learning algorithm can be employed as a decision support service for the diagnosis of AD. This study included 98 elderly participants aged 60 years or older who visited the Seoul Asan Medical Center and the Korea Veterans Health Service. We administered a standard diagnostic assessment for diagnosing AD. DBAD and three panels of medical experts (ME) diagnosed participants with normal cognition (NC) or AD using T1-weighted magnetic resonance imaging. The accuracy (87.1% for DBAD and 84.3% for ME), sensitivity (93.3% for DBAD and 80.0% for ME), and specificity (85.5% for DBAD and 85.5% for ME) of both DBAD and ME for diagnosing AD were comparable; however, DBAD showed a higher trend in every analysis than ME diagnosis. DBAD may support the clinical decisions of physicians who are not specialized in AD; this may enhance the accessibility of AD diagnosis and treatment.

Association of Low Emotional and Tangible Support With Risk of Dementia Among Adults 60 Years and Older in South Korea.

Importance: The association between social support and dementia risk has been debated. Most previous prospective studies have not differentiated the subtypes of social support. Objective: To examine whether the association between social support and risk of dementia differs by subtype of social support and by sex. Design, Setting, and Participants: This nationwide prospective cohort study included randomly sampled South Korean adults 60 years or older. The study was launched November 1, 2010, with follow-up every 2 years until November 30, 2020. The 5852 participants who completed the assessment for social support and were not diagnosed as having dementia, severe psychiatric disorders including major depressive disorder, or major neurological disorders at the baseline assessment were included in the analysis. Exposures: Geriatric psychiatrists administered the structured diagnostic interviews and physical examinations to every participant based on the Korean version of the Consortium to Establish a Registry for Alzheimer Disease (CERAD-K) Assessment Packet Clinical Assessment Battery. Main Outcomes and Measures: Baseline levels of emotional and tangible support using the Medical Outcomes Survey Social Support Survey. Results: Among the 5852 participants (mean [SD] age, 69.8 [6.6] years; 3315 women [56.6%]; mean [SD] follow-up duration, 5.9 [2.4] years), 237 (4.0%) had incident all-cause dementia and 160 (2.7%) had incident Alzheimer disease (AD) subtype of dementia. Compared with women who reported having emotional support, those with low emotional support had almost a 2-fold higher incidence of all-cause dementia (18.4 [95% CI, 13.6-23.2] vs 10.7 [95% CI, 9.0-12.5] per 1000 person-years) and AD (14.4 [95% CI, 10.2-18.6] vs 7.8 [95% CI, 6.3-9.3] per 1000 person-years). Adjusted Cox proportional hazard analysis revealed that low emotional support was associated with increased risk of all-cause dementia (hazard ratio, 1.61 [95% CI, 1.10-2.36]; P = .02) and AD (hazard ratio, 1.66 [95% CI, 1.07-2.57]; P = .02) only in women. Low tangible support was not associated with a risk of all-cause dementia or AD regardless of sex. Conclusions and Relevance: The findings of this cohort study suggest that older women with low emotional support constitute a population at risk for dementia. The level of emotional support should be included in risk assessments of dementia.

ES-RED (Early Seizure Recurrence in the Emergency Department) Calculator: A Triage Tool for Seizure Patients.

Seizure is a common neurological presentation in patients visiting the emergency department (ED) that requires time for evaluation and observation. Timely decision and disposition standards for seizure patients need to be established to prevent overcrowding in the ED and achieve patients' safety. Here, we conducted a retrospective cohort study to predict early seizure recurrence in the ED (ES-RED). We randomly assigned 688 patients to the derivation and validation cohorts (2:1 ratio). Prediction equations extracted routine clinical and laboratory information from EDs using logistic regression (Model 1) and machine learning (Model 2) methods. The prediction equations showed good predictive performance, the area under the receiver operating characteristics curve showing 0.808 in Model 1 [95% confidential interval (CI): 0.761-0.853] and 0.805 in Model 2 [95% CI: 0.747-0.857] in the derivation cohort. In the external validation, the models showed strong prediction performance of 0.739 [95% CI: 0.640-0.824] in Model 1 and 0.738 [95% CI: 0.645-0.819] in Model 2. Intriguingly, the lowest quartile group showed no ES-RED after 6 h. The ES-RED calculator, our proposed prediction equation, would provide strong evidence for safe and appropriate disposition of adult resolved seizure patients from EDs, reducing overcrowding and delays and improving patient safety.

Association between serum free hemoglobin level and cerebral white matter hyperintensity volume in older adults.

The association between serum free hemoglobin (sfHb) level and white matter hyperintensity (WMH) volume is controversial. This study is to examine this association considering nonlinearity, sex dimorphism, and WMH type. We enrolled 704 older adults among the participants of the Korean Longitudinal Study on Cognitive Aging and Dementia and visitors to the Dementia Clinic of Seoul National University Bundang Hospital. We measured sfHb level in the venous blood and WMH volume (VWMH) using fluid-attenuated inversion recovery magnetic resonance images. The association between sfHb level and periventricular VWMH was linear in men (linear regression; ß = - 0.18, p = 0.006) and U-shaped in women (restricted cubic spline; F = 6.82, p < 0.001). sfHb level was not associated with deep VWMH in either sex. These findings were also observed in participants without anemia. To conclude, sfHb level is associated with periventricular VWMH in older adults of both sexes. Maintaining an optimal sfHb level may contribute to the prevention of WMH.

Mood disorders increase mortality mainly through dementia: A community-based prospective cohort study.

OBJECTIVE: The effects of mood disorders on mortality may be mediated by their effects on the risk of dementia, and interventions to reduce the occurrence of dementia may reduce their overall mortality. This study aimed to investigate the direct effects of depressive and bipolar disorders on the 6-year risk of mortality and also their indirect effects on mortality due to their effect on the risk of dementia. METHODS: A total of 5101 Koreans were selected from a community-based prospective cohort study, and 6-year risks of mortality and dementia in participants with depressive and bipolar disorders were estimated by Cox proportional hazard analysis. The direct and indirect effects of depressive and bipolar disorders on the risk of mortality were estimated using structural equation modeling. RESULTS: The depressive and bipolar disorder groups showed 51% and 85% higher 6-year mortality, and 82% and 127% higher risk of dementia, respectively, compared to euthymic controls. The effects of depressive and bipolar disorders on mortality were mainly mediated by their effects on the risk of dementia in a structural equation model. The direct effects of each mood disorder on mortality were not significant. CONCLUSION: Both depressive and bipolar disorders increased the risks of mortality and dementia, and the effects of mood disorders on mortality were mainly mediated through dementia. As dementia occurs later in life than mood disorders, measures to prevent it may effectively reduce mortality in individuals with a history of mood disorders, as well as being more feasible than attempting to control other causes of death.

Exploration of Cognitive Outcomes and Risk Factors for Cognitive Decline Shared by Couples.

Importance: Although couples could share many risk factors of cognitive disorders in their lifetime, whether shared risk factors mediate the shared risk of cognitive disorders has rarely been investigated. Objective: To identify the risk factors of cognitive decline shared within couples and investigate their mediating roles in the shared risk of cognitive disorders and cognitive functions within couples. Design, Setting, and Participants: A prospective cohort study was launched in November 1, 2010, and 784 participants were followed up every 2 years until December 31, 2020. This nationwide, multicenter, community-based study included older couples from the Korean Longitudinal Study on Cognitive Aging and Dementia (KLOSCAD) and a cohort of their spouses (KLOSCAD-S). Exposures: The cognitive disorder of a spouse was defined as mild cognitive impairment or dementia. Main Outcomes and Measures: The mediating roles of factors shared within couples on the association between one spouse's cognitive disorder and the other's risk of cognitive disorders was examined with structural equation modeling. Results: Included were 784 KLOSCAD participants (307 women [39.2%] and 477 men [60.8%]; mean [SD] age, 74.8 [4.8] years) and their spouses (477 women [60.8%] and 307 men [39.2%]; mean [SD] age, 73.6 [6.2] years). The cognitive disorder of the KLOSCAD participants was associated with almost double the risk of cognitive disorder of their spouses in the KLOSCAD-S cohort (odds ratio, 1.74; 95% CI, 1.12-2.69; P = .01). History of head injury (ß = 0.50; 95% CI, 0.09-0.90; P = .02) and age (ß = 2.57; 95% CI, 1.37-3.76; P < .001) mediated the association between cognitive disorder in the KLOSCAD participants and their spouses' risk of cognitive disorder. Physical inactivity mediated the association through major depressive disorder (ß = 0.33, 95% CI, 0.09-0.57, P = .006 for physical inactivity; ß = 0.28, 95% CI, 0.13-0.44, P < .001 for major depressive disorder). These factors similarly mediated the association between spousal cognitive disorder and cognitive functions such as memory and executive function. Conclusions and Relevance: These findings suggest that the risk factors shared within couples may mediate approximately three-quarters of the spousal risk of cognitive disorders. Identification of and intervention in the shared risk factors of dementia within couples may reduce the risk of cognitive disorders in the spouses of people with dementia.

Aurora kinase A inhibition reverses the Warburg effect and elicits unique metabolic vulnerabilities in glioblastoma.

Aurora kinase A (AURKA) has emerged as a drug target for glioblastoma (GBM). However, resistance to therapy remains a critical issue. By integration of transcriptome, chromatin immunoprecipitation sequencing (CHIP-seq), Assay for Transposase-Accessible Chromatin sequencing (ATAC-seq), proteomic and metabolite screening followed by carbon tracing and extracellular flux analyses we show that genetic and pharmacological AURKA inhibition elicits metabolic reprogramming mediated by inhibition of MYC targets and concomitant activation of Peroxisome Proliferator Activated Receptor Alpha (PPARA) signaling. While glycolysis is suppressed by AURKA inhibition, we note an increase in the oxygen consumption rate fueled by enhanced fatty acid oxidation (FAO), which was accompanied by an increase of Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α). Combining AURKA inhibitors with inhibitors of FAO extends overall survival in orthotopic GBM PDX models. Taken together, these data suggest that simultaneous targeting of oxidative metabolism and AURKAi might be a potential novel therapy against recalcitrant malignancies.

The Impact of the COVID-19 Pandemic on Tourists' WTP: Using the Contingent Valuation Method.

This study estimated tourists' willingness to pay (WTP) for tourist sites or facilities in the prolonged COVID-19 pandemic by applying the dichotomous choice-contingent valuation method to two different tourism destination types. A survey was conducted among domestic tourists in South Korea who had visited destinations within the last six months. We conducted a logistic regression with 1283 effective samples. The results showed differences in tourists' WTP, depending on type, and the factors affecting WTP differed. Tourists with higher tourism attitude and knowledge of tourism risk exhibited a higher WTP. Tourists with higher perceived risk of infectious disease exhibited less WTP.