Relationship between rheological properties, sensory perception, and overall acceptability of thickened liquids for dysphagia in young and old healthy individuals.

This study investigated the relationship between rheological properties, sensory perception, and overall acceptability in healthy young and old groups for dysphagia thickened liquids. Unflavored (UTL) and flavored (FTLP) thickened liquids were prepared using tap water or pomegranate juice at 10 different viscosity levels. The rheological properties were then evaluated via syringe flow test and line spread test (LST). When the apparent viscosity levels of UTL and FTLP were similar, the syringe test and LST results were also similar, indicating consistent flow behavior. Sensory perception evaluations showed that the young group better distinguished viscosity differences between stages compared to the old group. Regarding overall acceptability, the old group preferred samples with higher apparent viscosity than the young group. Principal component analysis and k-means cluster analysis were used to explore correlations between variables and classify thickened liquids into four groups. This can serve the foundation for standardized texture grades of dysphagia thickened liquids, considering rheological characteristics and sensory profiles.

Comprehensive transcriptome profiling between balding and non-balding scalp of female pattern hair loss in Asian.

While many gene expression studies have focused on male pattern baldness (MPB), few studies have investigated the genetic differences between bald and non-bald hair follicles in female pattern hair loss (FPHL). This study aimed to identify molecular biomarkers associated with FPHL through genetic analysis of paired bald and non-bald hair follicles from 18 FPHL patients, using next-generation sequencing (NGS) techniques. RNA transcriptome analysis was performed to identify differentially expressed genes (DEGs) between bald and non-bald hair follicles in FPHL. The DEGs were validated using real-time PCR, and protein expression was confirmed through immunohistochemistry and western blot analysis. Our findings suggest that HOXB13, SFRP2, PTGDS, CXCR3, SFRP4, SOD3, and DCN are significantly upregulated in bald hair follicles compared to non-bald hair follicles in FPHL. SFRP2 and PTGDS were found to be consistently highly expressed in bald hair follicles in all 18 samples. Additionally, elevated protein levels of SFRP2 and PTGDS were confirmed through western blot and immunohistochemical analysis. Our study identified SFRP2 and PTGDS as potential biomarkers for FPHL and suggests that they may play a role in inducing hair loss in this condition. These findings provide a foundation for further research on the pathogenesis of FPHL and potential therapeutic targets.

Liquid collagen from freshwater fish skin ameliorates hydration, roughness and elasticity in photo-aged skin: a randomized, controlled, clinical study.

BACKGROUND/OBJECTIVES: Collagen is commonly used in diverse forms as a functional component in skincare products. On the other hand, the effects of collagen on human skin are controversial. Dietary collagen hydrolysates from freshwater Pangasius hypophthalmus fish skin ameliorated photo-aged skin of hairless mice. This study conducted a randomized, double-blind, placebo-controlled clinical trial to determine if liquid fish collagen (Collagen-Tripep20™, Tripep20) as a drink strengthens skin health and quality. SUBJECTS/METHODS: In this clinical trial, 85 subjects aged 35-60 yrs were diagnosed with photo-aged skin. Eighty-five subjects were randomized to receive either Tripep20 (n = 44) or placebo (n = 41). Seventy-eight subjects fully participating for a 12-week period consumed 1,000 mg of Tripep20 (n = 41) or placebo (n = 37) in a 50-mL bottle as a daily drink. The intend-to-treat and per-protocol populations were 85 and 78, respectively. Skin hydration, wrinkles, and elasticity were assessed at 0 (baseline), 6, and 12 weeks during the study period. RESULTS: Skin hydration in the Tripep20 group was significantly higher from 6 weeks (P < 0.001) than the baseline. After 12 weeks, the Crow's-feet visual score and skin roughness (Ra, Rq, and Rmax) were significantly improved in the Tripep20 group than in the placebo group (P < 0.05). Consuming liquid collagen Tripep20 greatly enhanced skin elasticity (Gross R2, Net R5, and Biological elasticity R7) in 6 weeks compared to the placebo group. The Tripep20 group showed a significant increase in skin elasticity from the baseline after 6 and 12 weeks (P < 0.001). Neither abnormal symptoms nor adverse events were encountered during the study period in subjects ingesting Tripep20 or placebo. The changes in parameters related to hematology and clinical chemistry were within the normal ranges. CONCLUSION: Oral consumption of liquid collagen Tripep20 was safe and well-tolerated. The results of this study show that freshwater fish-derived liquid collagen Tripep20 can be used as a healthy functional food ingredient to improve skin moisturizing, anti-wrinkling, and elasticity in an aging population.

Association between Water Intake and Abdominal Obesity: The Korea National Health and Nutrition Examination Survey 2019-2021.

Background: This study aimed to determine the link between water consumption and abdominal obesity in individuals aged 19 years and above, utilizing a sample from the 8th Korea National Health and Nutrition Examination Survey. Methods: Participants were divided into two groups based on their water intake: those meeting adequate intake (≥5 cups for men and ≥4 cups for women) and those with inadequate intake (<5 cups for men and <4 cups for women). Multivariate logistic regression analysis was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs), adjusted for potential confounders. Results: Compared with the inadequate water intake group, the adequate water intake group showed a lower adjusted OR for abdominal obesity (adjusted OR, 0.874; 95% CI, 0.770-0.992). In the subgroup analysis, the adjusted OR for abdominal obesity in the 19-39 age group was 0.712 (95% CI, 0.520-0.974). However, no significant association was observed in the 40-64 and 65 or higher age groups. Conclusion: Our findings indicate that sufficient water consumption may be negatively associated with abdominal obesity in adults, particularly among young adults; however, this association may not extend to older age groups.

Femoral anteversion linked to the inability to squat: Analysis of CT images in the patient and control groups.

Many patients who cannot squat well in a neutral toe position can only squat in an excessively out-toeing position. This excessive out-toeing squat is thought to be caused by rotational problems of the lower extremities. In this study, we aimed to identify the cause for the inability to squat by measuring and comparing femoral and tibial torsion between an excessive out-toeing squat patient group and a control group representing the general population. Between 2008 and 2022, a patient group comprising 50 lower extremities with excessive out-toeing squats was established. A control group representing the general population was selected from patients aged 0 to 29 years, who underwent lower-extremity CT angiography between 2012 and 2022, using the Clinical Data Warehouse with exclusion criteria applied. A total of 94 lower extremities were included in the control group. The femoral torsional angle (FTA) and tibial torsional angle (TTA) of both groups were measured and compared using Student t test. Additionally, 30 each of those with the highest and lowest 30 FTA values were selected from the patient and control groups, and the TTA was compared between the high- and low-FTA groups using Student t test. The mean FTA was 0.34° (SD, 11.11°) in the patient group and 10.14° (SD, 11.85°) in the control group, with a mean difference of 9.8° and P < .001. The mean TTA was 27.95° (SD, 7.82°) in the patient group and 32.67 ° (SD, 7.58°) in the control group, with a mean difference of 4.72° (P = .001). The mean TTA was 34.3° (SD, 7.72°) in the high-FTA group and 28.17° (SD, 8.35°) in the low-FTA group, with a mean difference of 6.13° (P = .005). Patients with excessive out-toeing squat showed lower FTA and TTA values than the general population. Furthermore, although a correlation between FTA and TTA was not established through Pearson correlation analysis, a tendency was observed where a decrease in FTA was associated with a decrease in TTA. Based on these results, decreased FTA was demonstrated to be one of the major causes of excessive out-toeing squats.

Evidence of the existence of multiple modules for the stroke-caused flexion synergy from Fugl-Meyer assessment scores.

Stroke-caused synergies may result from preferential use of the reticulospinal tract (RST) due to damage to the corticospinal tract. The RST branches multiple motoneuron pools across the arm together resulting in gross motor control or muscle synergies, and accordingly the controllability of individual muscles is reduced. It is not clear whether the muscles involuntarily activated by abnormal synergy vary with the muscles voluntarily activated when motor commands descend through the RST. Studies showed that abnormal synergies may originate from merging and re-weighting of synergies individuals without neurological deficit. This leads to a hypothesis that those abnormal synergies are still selectively excited depending on the context. In this study, we test this hypothesis, leveraging the Fugl-Meyer assessment (FMA) that could characterize the neuroanatomical architecture in individuals with a wide range of impairment. We examine the ability to perform an out-of-synergy movement with the flexion synergy caused by either shoulder or elbow loading. The results reveal that about 14% (8/57, 95%CI: [5.0%, 23.1%]) of the participants with severe impairment (total FM score <29) in the chronic phase (6 months after stroke) are able to keep the elbow extended during shoulder loading and keep the shoulder at neutral during elbow loading. Those participants undergo a different course of neural reorganization which enhanced abnormal synergies in comparison with individuals with mild impairment (p<0.05). These results evidence that separate routes and synergy modules to motoneuron pools across the arm might exist even if the motor command is mediated possibly via the RST.

Contrast-enhanced ultrasound features as potential biomarker for prediction of breast cancer recurrence.

Purpose To investigate the associations between contrast-enhanced ultrasound imaging features and disease recurrence among patients with locally advanced breast cancer treated with neoadjuvant chemotherapy. Materials and Methods In the study, pre- and post-neoadjuvant chemotherapy contrast-enhanced ultrasound images of 43 patients with breast cancer were retrospectively analysed. Post-acquisition image processing involved the placement of freehand-drawn regions of interest, followed by the generation of blood flow kinetics representing blood volume and velocity for these regions of interest. Qualitative and quantitative contrast-enhanced ultrasound parameters were compared to predict recurrence, and receiver operating characteristic analysis was used to evaluate predictive ability. Results Among the 43 patients, 10 (23%) exhibited disease recurrence (median [range]: 27 [4-68] months). Post-neoadjuvant chemotherapy peak enhancement, wash-in area under the curve, wash-out area under the curve, and wash-in and wash-out area under the curve (p=0.003, p=0.004, p=0.026, and p=0.014, respectively) differed between the no-recurrence and recurrence groups. The area under the receiver operating characteristic curve (0.88; 95% confidence interval: 0.75-1.00) for post-neoadjuvant chemotherapy peak enhancement was the highest among the contrast-enhanced ultrasound parameters, with a cut-off of 13.33 arbitrary units. Conclusion Higher peak enhancement on post-neoadjuvant chemotherapy contrast-enhanced ultrasound images were associated with recurrence in women with locally advanced breast cancer and is a potential biomarker of tumour recurrence.

Survey of patient satisfaction with genetic counseling services in Korea.

Since the 1990s, genetic clinics have been established in South Korea, enabling the provision of clinical genetics services. However, genetic counseling services are not widely used in the medical system. In contrast, recently, the demand for genetic counseling has increased due to the rapid development of genomic medicine. Therefore, it is important for medical geneticists and genetic counselors to collaboratively provide genetic counseling services. This study aimed to evaluate the perception and satisfaction of patients with rare genetic diseases and their families regarding genetic counseling services provided by a genetics team at the medical genetics center of a tertiary general hospital for rare genetic diseases. From April to November 2021, a survey was conducted with 203 individuals, including 111 and 92 individuals in the patient and family groups, respectively. Overall, 164 individuals (80.8%) responded that they were aware of genetic counseling services, and 135 individuals (66.5%) responded that they were aware of the role of genetic counselors. Patients and their families wanted to receive information about the following from genetic counseling: clinical manifestation and prognosis of the diagnosed disease (78.8%), treatment and management of the disease (60.6%), risk of recurrence within the family (55.7%), treatment options and alternatives for family and prenatal testing, and various support services. The score of satisfaction with genetic counseling services provided by the genetics team was 8.19 ± 1.68 out of 10. Patients with rare genetic diseases and their families were satisfied with genetic counseling services regarding their diseases, test results, and treatment options. Moreover, the patients could receive psychosocial support and referrals to other medical service providers and support services. As a genetic team approach, collaboration between medical geneticists and certified genetic counselors would be useful in providing information and in diagnosing, treating, and managing patients.

Remodeling of sorafenib as an orally bioavailable ferroptosis inducer for Lung Cancer by chemical modification of adenine-binding motif.

Sorafenib (BAY 43-9006) was developed as a multi-kinase inhibitor to treat advanced renal cell, hepatocellular, and thyroid cancers. The cytotoxic effect of sorafenib on cancer cells results from not only inhibiting the MEK/ERK signaling pathway (the on-target effect) but also inducing oxidative damage (the off-target effect). The inhibitory effect of sorafenib on system Xc- (xCT), a cystine/glutamate antiporter, promotes ferroptosis induction and accounts for oxidative damage. While emerging studies on ferroptosis in cancers have garnered increasing attention, the lack of consideration for ferroptosis inducers (FINs) with favorable pharmacokinetics could be problematic. Herein, we remodeled the chemical structure of sorafenib, of which pharmacokinetics and safety are already assured, to customize the off-target effect (i.e., ferroptosis induction) to on-target by disrupting the adenine-binding motif. JB3, a sorafenib derivative (i.e., JB compounds), with a tenfold higher IC50 toward RAF1 because of chemical remodeling, induced strong cytotoxicity in the elastin-sensitive lung cancer cells, while it was markedly reduced by ferrostatin-1. The 24% oral bioavailability of JB3 in rats accounted for a significant anti-tumor effect of orally administrated JB3 in xenograft models. These results indicate that JB3 could be further developed as an orally bioavailable FIN in novel anti-cancer therapeutics.

Pharmacological inhibition of p300 ameliorates steatosis, inflammation, and fibrosis in mice with non-alcoholic steatohepatitis.

The histone acetyltransferase p300 plays a pivotal role in regulating gene expression and cellular phenotype through epigenetic mechanisms. It significantly influences lipid metabolism, which is a key factor in the pathogenesis of non-alcoholic steatohepatitis (NASH), by modulating the transcription of genes involved in lipid synthesis and accumulation. This study aimed to investigate the protective potential of inhibiting p300 in NASH. Male C57BL/6J mice were subjected to a methionine- and choline-deficient (MCD) diet for 4 weeks to induce NASH, and during this period, the p300 inhibitor C646 (10 mg/kg) was administered three times a week. C646 treatment reduced the elevation of p300 expression and histone H3 acetylation, leading to a decrease in liver injury markers in the serum and an improvement in the histological abnormalities observed in MCD diet-fed mice. C646 also reduced lipid accumulation by modulating de novo lipogenesis and suppressed inflammation, including cytokine overproduction and macrophage infiltration. Furthermore, C646 mitigated liver fibrosis and myofibroblast accumulation. This protective effect was achieved through the inhibition of apoptosis by reducing p53 and Bax expression and the suppression of ferroptosis by decreasing lipid peroxidation while enhancing antioxidant defenses. Additionally, C646 alleviated endoplasmic reticulum stress, as evidenced by the downregulation of unfolded protein response signaling molecules. These results highlight the potential of p300 as a therapeutic target for NASH.

Sufficient water intake maintains the gut microbiota and immune homeostasis and promotes pathogen elimination.

Water is the most abundant substance in the human body and plays a pivotal role in various bodily functions. While underhydration is associated with the incidence of certain diseases, the specific role of water in gut function remains largely unexplored. Here, we show that water restriction disrupts gut homeostasis, which is accompanied by a bloom of gut microbes and decreased numbers of immune cells, especially Th17 cells, within the colon. These microbial and immunological changes in the gut are associated with an impaired ability to eliminate the enteric pathogen Citrobacter rodentium. Moreover, aquaporin 3, a water channel protein, is required for the maintenance of Th17 cell function and differentiation. Taken together, adequate water intake is critical for maintaining bacterial and immunological homeostasis in the gut, thereby enhancing host defenses against enteric pathogens.

Correlations in abnormal synergies between the upper and lower extremities across various phases of stroke.

BACKGROUND AND OBJECTIVES: The flexion synergy and extension synergy are a representative consequence of a stroke and appear in the upper extremity and lower extremity. Since the ipsilesional corticospinal tract (CST) is the most influential neural pathway for both extremities in motor execution, damage by a stroke to this tract could lead to similar motor pathological features (e.g., abnormal synergies) in both extremities. However, less attention has been paid to the inter-limb correlations in the flexion synergy and extension synergy across different recovery phases of a stroke. METHODS: We used results of the Fugl-Meyer assessment (FMA) to characterize those correlations in a total of 512 participants with hemiparesis post stroke from the acute phase to 1 year. The FMA provides indirect indicators of the degrees of the flexion synergy and extension synergy post stroke. RESULTS: We found that generally, strong inter-limb correlations (r>0.65 with all p-values<0.0001) between the flexion synergy and extension synergy appeared in the acute-to-subacute phase (<90 days). But correlations of lower-extremity extension synergy with upper-extremity flexion synergy and extension synergy decreased (down to r=0.38) around 360 days after stroke (p<0.05). DISCUSSION: These results suggest that preferential use of alternative neural pathways after damage by a stroke to the CST enhances inter-limb correlations between the flexion synergy and extension but a recovery of the CST functional and the fragmentation (remodeling) of the alternative neural substrates in the chronic phase contribute to diversity in neural pathways in motor execution, eventually leading to reduced inter-limb correlations.

LncRNA EIF3J-DT promotes chemoresistance in oral squamous cell carcinoma.

OBJECTIVES: This study aimed to screen oral squamous cell carcinoma (OSCC) diagnostic and prognostic candidates and investigate the potential functions and mechanisms of candidates in the chemoresistance of OSCC cell lines. MATERIALS AND METHODS: Differential expression profiling of lncRNA was performed in a large cohort of OSCC patients from the Cancer Genome Atlas database to identify OSCC diagnostic and prognostic candidates. Taxol resistance in OSCC cell lines was analyzed using MTT assay. OSCC cell lines transfected with EIF3J-DT pcDNA or siRNA were used to determine its regulatory effects on apoptosis, cell cycle distribution and autophagy using flow cytometry and western blot. RESULTS: We identified EIF3J-DT as a candidate for OSCC diagnosis and prognosis. The expression level of EIF3J-DT in OSCC cell lines correlates with taxol resistance. EIF3J-DT silencing attenuated taxol resistance, and EIF3J-DT overexpression enhanced taxol resistance in OSCC cell lines. Silencing of EIF3J-DT reduced taxol resistance by inducing apoptosis, cell cycle arrest, and ATG14-mediated autophagy inhibition in OSCC cell lines. CONCLUSIONS: We found that EIF3J-DT induced chemoresistance by regulating apoptosis, cell cycle, and autophagy in OSCC cell lines, which EIF3J-DT might provide a novel therapeutic approach for OSCC as well as a diagnostic and prognostic factor.

Heart Transplantation in a Patient With Rheumatic Heart Disease and Severe Left Atrial Calcification.

A 62-year-old woman who had undergone mitral valve replacement 24 years ago was admitted to the hospital with congestive heart failure. She needed heart transplantation for stage D heart failure. Preoperative cardiac computed tomographic scans showed a severely calcified left atrium and a large right atrium. Given that the left atrium's calcification was too severe to suture, the calcified left atrial wall was broadly resected, and the resected left atrial wall was reconstructed with a bovine pericardial patch for anastomosis with the donor's left atrial wall. The operation was completed without heavy bleeding, and the patient was discharged from the hospital with no complications.

Executive Summary of 2023 International Conference of the Korean Dementia Association (IC-KDA 2023): A Report From the Academic Committee of the Korean Dementia Association.

The Korean Dementia Association (KDA) has been organizing biennial international academic conferences since 2019, with the International Conference of the KDA (IC-KDA) 2023 held in Busan under the theme 'Beyond Boundaries: Advancing Global Dementia Solutions.' The conference comprised 6 scientific sessions, 3 plenary lectures, and 4 luncheon symposiums, drawing 804 participants from 35 countries. Notably, a Korea-Taiwan Joint Symposium addressed insights into Alzheimer's disease (AD). Plenary lectures by renowned scholars explored topics such as microbiome-related AD pathogenesis, social cognition in neurodegenerative diseases, and genetic frontotemporal dementia (FTD). On the first day, specific presentations covered subjects like the gut-brain axis and neuroinflammation in dementia, blood-based biomarkers in AD, and updates in AD therapeutics. The second day's presentations addressed recent issues in clinical neuropsychology, FTD cohort studies, and the pathogenesis of non-AD dementia. The Academic Committee of the KDA compiles lecture summaries to provide comprehensive understanding of the advanced dementia knowledge presented at IC-KDA 2023.

Enhancing genome editing in hPSCs through dual inhibition of DNA damage response and repair pathways.

Precise genome editing is crucial for establishing isogenic human disease models and ex vivo stem cell therapy from the patient-derived hPSCs. Unlike Cas9-mediated knock-in, cytosine base editor and prime editor achieve the desirable gene correction without inducing DNA double strand breaks. However, hPSCs possess highly active DNA repair pathways and are particularly susceptible to p53-dependent cell death. These unique characteristics impede the efficiency of gene editing in hPSCs. Here, we demonstrate that dual inhibition of p53-mediated cell death and distinct activation of the DNA damage repair system upon DNA damage by cytosine base editor or prime editor additively enhanced editing efficiency in hPSCs. The BE4stem system comprised of p53DD, a dominant negative p53, and three UNG inhibitor, engineered to specifically diminish base excision repair, improves cytosine base editor efficiency in hPSCs. Addition of dominant negative MLH1 to inhibit mismatch repair activity and p53DD in the conventional prime editor system also significantly enhances prime editor efficiency in hPSCs. Thus, combined inhibition of the distinct cellular cascades engaged in hPSCs upon gene editing could significantly enhance precise genome editing in these cells.

Retrospective analysis on prognosis of oral cancer patients according to surgical approaches for effective cancer ablation: swing approach versus visor approach.

BACKGROUND: For the surgical treatment of oral cancer, it is sometimes necessary to expand intraoral access within the oral cavity. The "swing approach" that involves lip splitting of the mandible and temporary mandibular osteotomy and the "visor approach" that does not split the lower lip and mandible are mainly used. This study analyzed postoperative outcomes such as complications, recurrence rate, and survival rate by these two approaches. The goal of this study is to evaluate the surgical outcomes of patients using these two approaches, to propose effective perioperative management for oral cancer surgery, and to compare the prognosis of oral cancer patients. MATERIALS AND METHODS: From 2005 to 2020, 29 patients who underwent surgery at the Department of Oral and Maxillofacial Surgery of Pusan National University Dental Hospital for oral cancer lesions occurred in the mandible, floor of mouth, and tongue were selected for the study. Based on the surgical approach used, a chart review was conducted on various prognostic clinical factors such as the patients' sex and age, primary site, TNM stage, histopathologic grade, recurrence and metastasis, postoperative survival rate, adjuvant chemo-radiation therapy, satisfaction with aesthetics/function/swallowing, length of hospital stay, tracheostomy and its duration, and neck dissection and its type. Statistical analysis was conducted using SPSS 25.0 (SPSS Inc., Chicago, IL) through Fisher's exact t-test. RESULT: There was no statistically significant difference between two groups in terms of clinical and pathological findings, such as survival rate, the need for adjuvant therapies, and the local recurrence rate. Although better outcomes were observed in terms of function, aesthetics, and postoperative complications in the group with visor approach, there was still no statistically significant difference between two groups. However, the duration of hospital stay was shorter in the visor approach group. CONCLUSION: There was no statistically significant difference in clinical prognostic factors between the swing approach and the visor approach. Therefore, when choosing between the two approaches for the ablation of oral cancer, it is considered to select the surgical priority approach that can be easy access based on the size and location of the lesion. The visor approach had advantages of aesthetics and healing period.

Controlling Fluorination Density of Soluble Polyimide Gate Dielectrics and its Influence on Organic Crystal Growth and Device Operational Stability.

Fluorinated polyimides (PIs) are among the most promising candidates for gate dielectric materials in organic electronic devices because of their solution processability and outstanding chemical, mechanical, and thermal stabilities. Additionally, fluorine (F) substitution improves the electrical properties of PI thin films, such as enhanced dielectric properties and reduced surface trap densities. However, the relationship between the fluorination density of PIs and crystal growth modes of vacuum-deposited conjugated molecules on PI thin films, which is directly related to the lateral charge transport along the PI-organic semiconductor interface, has not been systematically studied. Herein, five different soluble PIs with different F densities were synthesized, and the correlation between fluorination and thin-film properties was systematically investigated. Not only were their dielectric properties modulated, but the growth modes of the organic molecules deposited on the PI thin films also changed with increasing surface F density. This phenomenon was observed by both surface and crystallographic analyses, which resulted in extremely high operational stability of field-effect transistors and the successful fabrication of organic complementary circuits. We believe that the correlation between PI backbone fluorination and its thin-film properties will provide practical insights into the material design based on controlled molecular directed surface assembly on fluorinated polymer dielectrics.

Dose-response analysis between alcohol consumption and psoriasis: A systematic review and meta-analysis.

The association between psoriasis and alcohol consumption has been inconsistent across various studies. However, to the best of our knowledge, no dose-response meta-analysis has been performed to date. This study aims to investigate the association between alcohol consumption and psoriasis. The search was performed on July 27, 2021, using Embase and MEDLINE. The restricted cubic spline analysis was used to perform a dose-response analysis. We identified 3,904 studies, of which 48 studies with 1,702,847 individuals across 24 countries were included. Alcohol consumption was positively associated with psoriasis (odds ratio [OR], 1.47; 95% confidence interval [CI], 1.27-1.70). In addition, a significantly increased OR for psoriasis was observed in males (OR, 1.84; 95% CI, 1.13-3.01) but not in females (OR, 1.22; 95% CI, 0.97-1.54). Based on eight studies, including three cohort and five case-control studies, the analysis revealed that with each additional gram of daily alcohol intake, the OR for psoriasis increased by 4%. We found a positive association between alcohol consumption and psoriasis. The association is more prominent in the group drinking more than 45 g of alcohol per day (3.2 alcoholic drink equivalent).

Structural determinants for activation of the Tau kinase CDK5 by the serotonin receptor 5-HT7R.

BACKGROUND: Multiple neurodegenerative diseases are induced by the formation and deposition of protein aggregates. In particular, the microtubule-associated protein Tau leads to the development of so-called tauopathies characterized by the aggregation of hyperphosphorylated Tau within neurons. We recently showed that the constitutive activity of the serotonin receptor 7 (5-HT7R) is required for Tau hyperphosphorylation and aggregation through activation of the cyclin-dependent kinase 5 (CDK5). We also demonstrated physical interaction between 5-HT7R and CDK5 at the plasma membrane suggesting that the 5-HT7R/CDK5 complex is an integral part of the signaling network involved in Tau-mediated pathology. METHODS: Using biochemical, microscopic, molecular biological, computational and AI-based approaches, we investigated structural requirements for the formation of 5-HT7R/CDK5 complex. RESULTS: We demonstrated that 5-HT7R domains responsible for coupling to Gs proteins are not involved in receptor interaction with CDK5. We also created a structural model of the 5-HT7R/CDK5 complex and refined the interaction interface. The model predicted two conserved phenylalanine residues, F278 and F281, within the third intracellular loop of 5-HT7R to be potentially important for complex formation. While site-directed mutagenesis of these residues did not influence Gs protein-mediated receptor signaling, replacement of both phenylalanines by alanine residues significantly reduced 5-HT7R/CDK5 interaction and receptor-mediated CDK5 activation, leading to reduced Tau hyperphosphorylation and aggregation. Molecular dynamics simulations of 5-HT7R/CDK5 complex for wild-type and receptor mutants confirmed binding interface stability of the initial model. CONCLUSIONS: Our results provide a structural basis for the development of novel drugs targeting the 5-HT7R/CDK5 interaction interface for the selective treatment of Tau-related disorders, including frontotemporal dementia and Alzheimer's disease.