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Headache, a highly prevalent neurological disorder, has consistently been linked with an elevated risk of dementia. However, most studies are focused on the relationship with migraine in limited age groups. Therefore, the objective of this research was to look at the link between various type of headaches and dementias based on longitudinal population-based data. Headache could be an independent predictor for subsequent dementia risk. Future studies should focus on clarifying pathogenic pathways and possible dementia-related preventive measures in headache populations.

Elucidating how individual mutations affect the protein energy landscape is crucial for understanding how proteins evolve. However, predicting mutational effects remains challenging because of epistasis—the nonadditive interactions between mutations. Here, we investigate the biophysical mechanism of strain-specific epistasis in the nonstructural protein 1 (NS1) of influenza A viruses (IAVs). We integrate structural, kinetic, thermodynamic, and conformational dynamics analyses of four NS1s of influenza strains that emerged between 1918 and 2004. Although functionally near-neutral, strain-specific NS1 mutations exhibit long-range epistatic interactions with residues at the p85β-binding interface. We reveal that strain-specific mutations reshaped the NS1 energy landscape during evolution. Using NMR spin dynamics, we find that the strain-specific mutations altered the conformational dynamics of the hidden network of tightly packed residues, underlying the evolution of long-range epistasis. This work shows how near-neutral mutations silently alter the biophysical energy landscapes, resulting in diverse background effects during molecular evolution. Influenza A virus (IAV) nonstructural protein 1 (NS1) is a multifunctional virulence factor that interacts with several host factors such as phosphatidylinositol-3-kinase (PI3K). NS1 binds specifically to the p85β regulatory subunit of PI3K and subsequently activates PI3K signaling. Here, Kim et al. show that functionally near-neutral, strain-specific NS1 mutations lead to variations in binding kinetics to p85β exhibit long-range epistatic interactions. Applying NMR they provide evidence that the structural dynamics of the NS1 hydrophobic core have evolved over time and contributed to epistasis.

Despite favorable responses to initial chemotherapy, drug resistance is a major cause limiting chemotherapeutic efficacy in many advanced cancers. However, mechanisms that drive drug-specific resistance in chemotherapy for patients with advanced cancers are still unclear. Here, we report a unique role of death-associated protein kinase-related apoptosis-inducing kinase 1 (DRAK1) associated with paclitaxel resistance in cervical cancer cells. Interestingly, DRAK1 protein level was markedly decreased in paclitaxel-resistant cervical cancer cells without affecting its mRNA expression, which resulted in an increase in tumor necrosis factor receptor-associated factor 6 (TRAF6) expression, as well as an activation of TRAF6-mediated nuclear factor-kappa B (NF-κB) signaling cascade, thereby promoting tumor progression. DRAK1 depletion markedly increased the chemotherapeutic IC 50 values of paclitaxel in cervical cancer cells. Ectopic expression of DRAK1 inhibited growth of paclitaxel-resistant cervical cancer cells in vitro and in vivo. Furthermore, DRAK1 was markedly underexpressed in chemoresistant cervical cancer patient tissues compared with chemosensitive samples. We found that DRAK1 protein was destabilized through K48-linked polyubiquitination promoted by the Cullin scaffold protein 3 (CUL3) / speckle-type POZ (poxvirus and zinc finger protein) protein (SPOP) E3 ubiquitin ligase in paclitaxel-resistant cells. Collectively, these findings suggest that DRAK1 may serve as a potential predictive biomarker for overcoming paclitaxel resistance in cervical cancer.

This study aimed to investigate the effect of interdental brushes and dental floss on the prevention of periodontitis in participants with ≥ 20 or < 20 remaining teeth by using the Korea National Health and Nutrition Examination Survey 2016–2018. Data from 11,614 participants were analysed using multivariate logistic regression after adjusting for sociodemographic factors (age and sex), socioeconomic factors (level of education and individual income), oral health-related variables (daily toothbrushing), and systemic health-related variables (smoking, diabetes, and obesity). The adjusted odds ratio (AOR) showed statistically significant results for both floss (AOR, 1.41; 95% confidence interval (CI) 1.22–1.64) and interdental brushes (AOR, 1.16; 95% CI 1.01–1.34). However, no significant difference was found in the subjects with fewer than 20 teeth. The subgroup analysis showed that interdental brushes had a significant preventive effect on women who had more than 20 teeth. Among participants with fewer than 20 teeth, interdental brush users had more periodontitis in men. Regarding those with more than 20 teeth, health inequality was alleviated when floss and interdental brushes were used. The bottom line is that the effect of preventing periodontitis in interdental brushes and dental floss was more evident in participants with ≥ 20 remaining teeth rather than in participants with < 20 remaining teeth.

Adolescence is a time when important changes occur in behavioral development, and previous studies have confirmed the relationship between excessive Internet use and decreased oral health behavior. Our purpose is to identify the indirect effects and behavioral factors of smartphone screen time on the caries symptom experience of adolescents. Using data from the 16–17th Korea youth risk behavior web based survey (2020–2021), we investigated the smartphone screen time of 109,796 students in middle school 1 st to high school 3 rd . Adolescents who used smartphones more than 6 h per week were 28% more likely to experience caries symptoms than those who used smartphones less than 2 h (odds ratio = 1.28; 95% confidence interval, 1.22–1.35). Those who consumed cariogenic drinks more than once a day were 25% more likely to experience caries symptoms, and those who brushed their teeth less than once a day were 26% more likely to experience caries symptoms (odds ratio = 1.25, 1.26; 95% confidence interval, 1.07–1.46, 1.06–1.51). Excessive smartphone screen time is associated with addictive eating habits and reduced physical activity that increase cariogenic dietary behaviors, and decrease oral health behaviors. It suggests that excessive smartphone use indirectly related to the experience of caries symptoms.

The 1918 influenza A virus (IAV) caused the worst flu pandemic in human history. Non-structural protein 1 (NS1) is an important virulence factor of the 1918 IAV and antagonizes host antiviral immune responses. NS1 increases virulence by activating phosphoinositide 3-kinase (PI3K) via binding to the p85β subunit of PI3K. Intriguingly, unlike the NS1 of other human IAV strains, 1918 NS1 hijacks another host protein, CRK, to form a ternary complex with p85β, resulting in hyperactivation of PI3K. However, the molecular basis of the ternary interaction between 1918 NS1, CRK, and PI3K remains elusive. Here, we report the structural and thermodynamic bases of the ternary interaction. We find that the C-terminal tail (CTT) of 1918 NS1 remains highly flexible in the complex with p85β. Thus, the CTT of 1918 NS1 in the complex with PI3K can efficiently hijack CRK. Notably, our study indicates that 1918 NS1 enhances its affinity to p85β in the presence of CRK, which might result in enhanced activation of PI3K. Our results provide structural insight into how 1918 NS1 hijacks two host proteins simultaneously.

We aimed to evaluate the risk of coronary heart disease (CHD) according to dental caries status in middle-aged patients using a population-based cohort database containing medical/dental claims, health examination, and death records in the Republic of Korea. A total of 234,597 patients were identified in the database who were without history of cardiovascular disease, including 104,638 patients without dental caries, 41,696 with incipient/moderate stage dental caries, and 88,262 advanced/severe dental caries. We used Cox proportional hazards model adjusted for sociodemographic, lifestyle, and medical characteristics to compute hazard ratio (HR) and 95% confidence intervals (95% CI) for CHD according to severity of dental caries. During 1,491,190 person-years of follow-up, there were a total of 6,015 CHD events. After adjustment for potential confounders, patients in the highest quartile of outpatient visits for advanced/severe stage dental caries was associated with an increase in CHD risk (HR = 1.13; 95% CI: 1.04–1.22) as compared with patients without dental caries. When the analysis was restricted to the patients with advanced/severe dental caries, dose-response relationship between number of outpatient visits for dental caries and risk of CHD was observed ( P trend : <0.001). Prevention and control of dental caries might be worth promoting in clinical practice to prevent CHD.

Liver cirrhosis is a major cause of mortality and a common end of various progressive liver diseases. Since the effective treatment is currently limited to liver transplantation, stem cell-based therapy as an alternative has attracted interest due to promising results from preclinical and clinical studies. However, there is still much to be understood regarding the precise mechanisms of action. A number of stem cells from different origins have been employed for hepatic regeneration with different degrees of success. The present review presents a synopsis of stem cell research for the treatment of patients with liver cirrhosis according to the stem cell type. Clinical trials to date are summarized briefly. Finally, issues to be resolved and future perspectives are discussed with regard to clinical applications.

Physical activity reduces the risk and mortality risk of inflammatory diseases. This study aimed to examine the relationship between regular walking and periodontitis in a Korean representative sample of adults according to socioeconomic status. Data acquired by the Sixth Korea National Health and Nutrition Examination Survey in 2014 and 2015 were used. The survey was completed by 11,921 (5,175 males; 6,746 females) participants (≥19 years). Individuals without values on periodontitis were excluded, and 9,728 participants remained. Multivariable logistic regression analysis was done using socio-demographic characteristics (age, gender, income, education), oral health-related variables (flossing, interdental brushing, community periodontal index), oral and general health status and behaviour (smoking, diabetes mellitus), and regular walking. In all models, subjects who walked regularly had significantly lower risks of periodontitis. After adjusting for age, gender, income, education, smoking, diabetes mellitus, flossing, and interdental brushing, the odds ratio for periodontitis in subjects who walked regularly was 0.793 (95% Confidence interval: 0.700–0.898). Non-regular walking groups showed similar social gradients. Risk of low socioeconomic status was not significant in the regular walking group after adjusting for age, gender, income, and education. This study found that regular walking is associated to lower prevalence of periodontitis and can attenuate the relationship between periodontitis and low socioeconomic status.

Unfolded and partially unfolded proteins participate in a wide range of biological processes from pathological aggregation to the regulation of normal cellular activity. Unfolded states can be populated under strongly denaturing conditions, but the ensemble which is relevant for folding, stability, and aggregation is that populated under physiological conditions. Characterization of nonnative states is critical for the understanding of these processes, yet comparatively little is known about their energetics and their structural propensities under native conditions. The standard view is that energetically significant coupled interactions involving multiple residues are generally not present in the denatured state ensemble (DSE) or in intrinsically disordered proteins. Using the N-terminal domain of the ribosomal protein L9, a small α-β protein, as an experimental model system, we demonstrate that networks of energetically significant, coupled interactions can form in the DSE of globular proteins, and can involve residues that are distant in sequence and spatially well separated in the native structure. X-ray crystallography, NMR, dynamics studies, native state pK ₐ measurements, and thermodynamic analysis of more than 25 mutants demonstrate that residues are energetically coupled in the DSE. Altering these interactions by mutation affects the stability of the domain. Mutations that alter the energetics of the DSE can impact the analysis of cooperativity and folding, and may play a role in determining the propensity to aggregate.