Gaining Insights into Key Structural Hotspots within the Allosteric Binding Pockets of Protein Kinases.

Protein kinases are essential regulators of cell function and represent one of the largest and most diverse protein families. They are particularly influential in signal transduction and coordinating complex processes like the cell cycle. Out of the 518 human protein kinases identified, 478 are part of a single superfamily sharing catalytic domains that are related in sequence. The dysregulation of protein kinases due to certain mutations has been associated with various diseases, including cancer. Although most of the protein kinase inhibitors identified as type I or type II primarily target the ATP-binding pockets of kinases, the structural and sequential resemblances among these pockets pose a significant challenge for selective inhibition. Therefore, targeting allosteric pockets that are beside highly conserved ATP pockets has emerged as a promising strategy to prevail current limitations, such as poor selectivity and drug resistance. In this article, we compared the binding pockets of various protein kinases for which allosteric (type III) inhibitors have already been developed. Additionally, understanding the structure and shape of existing ligands could aid in identifying key interaction sites within the allosteric pockets of kinases. This comprehensive review aims to facilitate the design of more effective and selective allosteric inhibitors.

School Nurses' Experiences and Needs in COVID-19 Pandemic Response: A Qualitative Study.

The coronavirus disease 2019 pandemic drastically shifted the public health burden onto the school health system. We, therefore, explored the school nurses' experiences and needs for confronting the pandemic in school settings across Korea. This qualitative investigation enrolled 30 participants after their written consent. A written interview conducted through email and focus group interviews using an online meeting application verified participants' opinions and experiences. Collected data were subjected to text-mining and content analysis. The school nurse was found to be responsible for many tasks, including education on preventive measures with unclear quarantine guidelines. Content analysis identified three key themes: "aggravated difficulties owing to lack of support resulted in burnout," "reflection on supportive resources; direct provisions were helpful," and "needs and suggestions to safeguard students' health in the event of another pandemic." Recommendations should all be considered to keep schools and students safe from future pandemics.

Expert Consensus on COVID-19 Vaccination in Korean Adolescents: A Modified Delphi Survey.

The effectiveness of coronavirus disease 2019 (COVID-19) vaccines had been shown in many studies in adult population, however, the real-world evidence in the childhood population was scarce. We aimed to organize the collective expert's opinions on adolescent vaccination against COVID-19 in Korea, therefore to guide the vaccination policy in the setting of available evidence. The Delphi panels responded that adolescents were greatly impacted by the quarantine measures, and COVID-19 is an important health problem for adolescents. Panels responded that in general, the benefits of the COVID-19 vaccine overweigh the potential risks in Korean adolescents. Continuing monitoring of available data is needed to provide the best vaccination practices in adolescents guided by the updated evidence.

Effects and Mechanism of Particulate Matter on Tendon Healing Based on Integrated Analysis of DNA Methylation and RNA Sequencing Data in a Rat Model.

Exposure to particulate matter (PM) has been linked with the severity of various diseases. To date, there is no study on the relationship between PM exposure and tendon healing. Open Achilles tenotomy of 20 rats was performed. The animals were divided into two groups according to exposure to PM: a PM group and a non-PM group. After 6 weeks of PM exposure, the harvest and investigations of lungs, blood samples, and Achilles tendons were performed. Compared to the non-PM group, the white blood cell count and tumor necrosis factor-alpha expression in the PM group were significantly higher. The Achilles tendons in PM group showed significantly increased inflammatory outcomes. A TEM analysis showed reduced collagen fibrils in the PM group. A biomechanical analysis demonstrated that the load to failure value was lower in the PM group. An upregulation of the gene encoding cyclic AMP response element-binding protein (CREB) was detected in the PM group by an integrated analysis of DNA methylation and RNA sequencing data, as confirmed via a Western blot analysis showing significantly elevated levels of phosphorylated CREB. In summary, PM exposure caused a deleterious effect on tendon healing. The molecular data indicate that the action mechanism of PM may be associated with upregulated CREB signaling.

Association of decreased grip strength with lower urinary tract symptoms in women: a cross-sectional study from Korea.

BACKGROUND: Lower urinary tract symptoms (LUTS) including frequency, nocturia, urgency, and incontinence, are common in women and cause significant discomfort in daily life. However, diagnosis and treatment of LUTS are often delayed because many patients with such symptoms do not complain to the physician of discomfort and do not seek medical attention. LUTS are known to be associated with muscle weakness. We investigated the association between grip strength and LUTS in women of different ages. METHODS: This study included 4225 women (mean age 48.6 years) who underwent self-referred health screening between April 2015 and December 2019. LUTS were evaluated using a self-reported questionnaire, and the overactive bladder symptom score was used to screen for an overactive bladder. Low muscle strength was defined as a hand grip strength of < 18 kg (decreased grip strength). RESULTS: We observed decreased grip strength in 13.7% (n = 580) of the participants. Nocturia, urgency, incontinence, and overactive bladder were more common in women with decreased grip strength than in women with normal grip strength. After adjusting for age, comorbidities (hypertension, diabetes, hyperlipidemia), smoking status, alcohol consumption, regular exercise, and stress, nocturia (odds ratio [OR] 1.19, 95% confidence interval [CI] 1.01-1.52), urinary incontinence (OR 1.32, 95% CI 1.01-1.72), and an overactive bladder (OR 1.75, 95% CI 1.35-2.27) were significantly associated with decreased grip strength. CONCLUSIONS: The findings suggest that LUTS, especially nocturia, incontinence, and an overactive bladder are associated with decreased grip strength in women. Therefore, physicians should be aware that patients may not seek help, even if they are uncomfortable, and it is important to obtain a detailed medical history and perform additional tests, even in the absence of complaints, in patients with low grip strength, who are at high risk of LUTS.

Health promotion program for office workers with SEM based on the WHO's healthy workplace framework.

This study attempts to develop and verify the effectiveness of a health promotion program for office workers based on the social ecological model and the World Health Organization's Healthy Workplace Framework. This study involved 272 office workers of a small and medium-sized enterprise in Korea. Data were analyzed through descriptive statistics, repeated measures analysis of variance (ANOVA) and Bonferroni correction using SPSS/WIN 23.0. Workplace environmental support was provided to all workers, while a 6-month intensive core program based on social support was implemented for the intensive management group. Based on the participation rate, individuals were divided into the core and dropout groups. In all office workers, there were negative changes in high-density lipoprotein cholesterol and job stress during the period. Meanwhile, the intensive group showed significant changes in body mass index and diastolic blood pressure. The study suggests that the organization's support for a healthy environment and an individual's continued participation based on social support are essential for the effectiveness of a health promotion program for office workers.

The Liguleless narrow mutation affects proximal-distal signaling and leaf growth.

How cells acquire competence to differentiate according to position is an essential question in developmental biology. Maize leaves provide a unique opportunity to study positional information. In the developing leaf primordium, a line is drawn across a field of seemingly identical cells. Above the line, the cells become blade, below the line the cells become sheath and at the line, the cells differentiate into the specialized tissues of ligule and auricle. We identified a new mutation, Liguleless narrow (Lgn), that affects this patterning and shows striking defects in lateral growth as well, thus linking proximal-distal patterning to medial-lateral growth. In characterizing the defect we discovered that both the auxin transport protein ZmPIN1a and the squamosa promoter-binding protein LIGULELESS1 are expressed precisely at this positionally cued line and are disrupted by Lgn. Positional cloning and a transposon-derived allele demonstrate that LGN is a kinase. These results suggest that LGN participates in setting up positional information through a signaling cascade. Interestingly, LGN has a paralog that is upregulated in the mutant, suggesting an important feedback mechanism involved in setting the positional boundary.

Regulation of cell divisions and differentiation by MALE STERILITY32 is required for anther development in maize.

Male fertility in flowering plants relies on proper division and differentiation of cells in the anther, a process that gives rise to four somatic layers surrounding central germinal cells. The maize gene male sterility32 (ms32) encodes a basic helix-loop-helix (bHLH) transcription factor, which functions as an important regulator of both division and differentiation during anther development. After the four somatic cell layers are generated properly through successive periclinal divisions, in the ms32 mutant, tapetal precursor cells fail to differentiate, and, instead, undergo additional periclinal divisions to form extra layers of cells. These cells become vacuolated and expand, and lead to failure in pollen mother cell development. ms32 expression is specific to the pre-meiotic anthers and is distributed initially broadly in the four lobes, but as the anther develops, its expression becomes restricted to the innermost somatic layer, the tapetum. The ms32-ref mac1-1 double mutant is unable to form tapetal precursors and also exhibits excessive somatic proliferation leading to numerous, disorganized cell layers, suggesting a synergistic interaction between ms32 and mac1. Altogether, our results show that MS32 is a major regulator in maize anther development that promotes tapetum differentiation and inhibits periclinal division once a tapetal cell is specified.

Dysfunctional adipocytes promote tumor progression through YAP/TAZ-dependent cancer-associated adipocyte transformation.

Obesity has emerged as a prominent risk factor for the development of malignant tumors. However, the existing literature on the role of adipocytes in the tumor microenvironment (TME) to elucidate the correlation between obesity and cancer remains insufficient. Here, we aim to investigate the formation of cancer-associated adipocytes (CAAs) and their contribution to tumor growth using mouse models harboring dysfunctional adipocytes. Specifically, we employ adipocyte-specific BECN1 KO (BaKO) mice, which exhibit lipodystrophy due to dysfunctional adipocytes. Our results reveal the activation of YAP/TAZ signaling in both CAAs and BECN1-deficient adipocytes, inducing adipocyte dedifferentiation and formation of a malignant TME. The additional deletion of YAP/TAZ from BaKO mice significantly restores the lipodystrophy and inflammatory phenotypes, leading to tumor regression. Furthermore, mice fed a high-fat diet (HFD) exhibit decreased BECN1 and increased YAP/TAZ expression in their adipose tissues. Treatment with the YAP/TAZ inhibitor, verteporfin, suppresses tumor progression in BaKO and HFD-fed mice, highlighting its efficacy against mice with metabolic dysregulation. Overall, our findings provide insights into the key mediators of CAA and their significance in developing a TME, thereby suggesting a viable approach targeting adipocyte homeostasis to suppress cancer growth.

A genetic link between cold responses and flowering time through FVE in Arabidopsis thaliana.

Cold induces expression of a number of genes that encode proteins that enhance tolerance to freezing temperatures in plants. A cis-acting element responsive to cold and drought, the C-repeat/dehydration-responsive element (C/DRE), was identified in the Arabidopsis thaliana stress-inducible genes RD29A and COR15a and found in other cold-inducible genes in various plants. C/DRE-binding factor/DRE-binding protein (CBF/DREB) is an essential component of the cold-acclimation response, but the signaling pathways and networks are mostly unknown. Here we used targeted genetic approach to isolate A. thaliana mutants with altered cold-responsive gene expression (acg) and identify ACG1 as a negative regulator of the CBF/DREB pathway. acg1 flowered late and had elevated expression of FLOWERING LOCUS C (FLC), a repressor of flowering encoding a MADS-box protein. We showed that acg1 is a null allele of the autonomous pathway gene FVE. FVE encodes a homolog of the mammalian retinoblastoma-associated protein, a component of a histone deacetylase (HDAC) complex involved in transcriptional repression. We also showed that plants sense intermittent cold stress through FVE and delay flowering with increasing expression of FLC. Dual roles of FVE in regulating the flowering time and the cold response may have an evolutionary advantage for plants by increasing their survival rates.

Development and psychometric testing of the Heart-Healthy Information Questionnaire.

AIMS: This study aimed to develop a reliable and valid scale, i.e. the Heart-Healthy Information Questionnaire (HHIQ). METHODS AND RESULTS: The HHIQ was developed in three phases: (i) creating the item pool, (ii) conducting a preliminary evaluating the items, and (iii) refining the scale and evaluating psychometric properties. An initial item pool of 77 items with a 3-point True/False format with a 'Don't know' option was extracted from the literature review and 54 items reached content validity. The psychometric properties of HHIQ were tested with 1315 individuals without cardiovascular disease. By using the exclusion criteria of the difficulty index (>0.95), discrimination index (<10.0), and item-total correlation (tetrachoric coefficient <0.2), 50 items were finally selected. The construct validity was determined by using the known-groups validation: Individuals (n = 107) who were educated with heart-healthy education sessions showed significantly higher scores of the HHIQ than those (n = 107) who were not educated (P = 0.015). The Kuder-Richardson formula 20 coefficient indicated good internal consistency (0.85), and the test-retest reliability coefficient with a 15-day interval also indicated good stability (0.78). A total score of the HHIQ was significantly correlated with a total score of the Evaluation Tool for Metabolic Syndrome Modification Lifestyles (ρ = 0.23, P < 0.001). CONCLUSION: The HHIQ showed good psychometric properties of validity and reliability and may be useful to evaluate the knowledge levels of heart-healthy information in the areas of cardiovascular disease prevention.

Current status and needs in the primary healthcare system in Yangon, Myanmar: a mixed-method evaluation.

BACKGROUND: Many low- and middle-income countries and international organisations have invested resources to strengthen primary health care (PHC). This study aimed to identify the challenges and unmet needs in the current PHC by assessing the experiences and perceptions of healthcare workers in three townships (Htan Ta Pin, Hmawbi, and Taikkyi) in Yangon, Myanmar. METHODS: The study was conducted among healthcare professionals and community leaders in three townships. Adopting a mixed-method approach, a cross-sectional health needs assessment survey was conducted for quantitative data (n = 66), and focus group discussions (FGDs) were conducted online for qualitative data. FINDINGS: Enhancing the management and leadership capacity had the lowest average score on the current achievement (2.81 out of 5 ratings) while strengthening infectious disease control service and accessibility was perceived as the highest mean on the priority of intervention (4.28) and the impact of the intervention (4.7). The FGDs revealed that while specific infrastructures and equipment were reported insufficient and necessary, the need for financial support has been the recurrent theme throughout the discussions. INTERPRETATION: Utilising the World Health Organisation's six building block frameworks, our findings suggest that a long-term targeted financial investment in the PHC system is critical in Myanmar through increasing healthcare expenditure per capita.

Soluble CD93 induces differentiation of monocytes and enhances TLR responses.

The cell surface protein CD93 is known to be involved in the regulation of phagocytosis and cell adhesion. Although typically membrane-bound, a soluble form of CD93 (sCD93) has recently been identified. Currently, however, the role of sCD93 in monocyte function is unknown. In the current study, we analyzed the functional effects of sCD93 on THP-1 monocytic cells and human primary monocytes. Various forms of recombinant human sCD93 were used to investigate the effects of this molecule on both human primary monocytes and a monocytic cell line, THP-1. We found that sCD93 induced differentiation of monocytes to macrophage-like cells, as evidenced by activated cell adhesion and increased phagocytic activities. In addition, this differentiation resulted in an enhanced response to TLR stimulation in terms of differentiation marker expression and proinflammatory cytokine production. Furthermore, sCD93 enhanced LPS-stimulated TNF-α production even prior to monocyte differentiation. To investigate a possible role for sCD93 in the pathogenesis of chronic inflammatory diseases, we assessed the concentration of sCD93 in synovial fluid from patients with rheumatoid arthritis and found it to be significantly increased compared with synovial fluid from patients with osteoarthritis. Together, these data revealed a function for sCD93 that may have implications in inflammation and inflammatory diseases including rheumatoid arthritis.

Investigation of bonding characteristics between Si quantum dots and a SiO2 matrix.

In order to understand and control the properties of Si quantum dot (QD) superlattice structures (SLS), it is necessary to investigate the bonding between the dots and their matrix and also the structures' crystallinities. In this study, a SiOx matrix system was investigated and analyzed for potential use as an all-silicon multi-junction solar cell. Si QD SLS were prepared by alternating deposition of Si rich SiOx (x = 0.8) and SiO2 layers using RF magnetron co-sputtering and subsequent annealing at temperatures between 800 and 1,100 degrees C under nitrogen ambient. Annealing temperatures and times affected the formation of Si QDs in the SRO film. Raman and FTIR spectra revealed that nanocrystalline Si QDs started to precipitate after annealing at 1,100 degrees C for 1 hour. TEM images clearly showed SRO/SiO2 SLS and Si QDs formation in SRO layers after annealing at 1,100 degrees C for 2 hours. XPS analysis showed that Si-Si and Si-O bonding changes occurred above 1,100 degrees C. XPS analysis also revealed that Si QD SLSs started stabilizing after 2 hours' annealing and approached completion after 3 hours'. The systematic investigation of Si QDs in SiO2 matrices and their properties for solar cell application are presented.

Intention to quit electronic cigarette smoking among university students who are e-cigarette users.

OBJECTIVE: To identify factors that are significantly associated with the intention to quit electronic cigarette smoking (ECS) at multiple, ecological levels among university students. PARTICIPANTS: 365 students who were e-cigarette users from Seoul metropolitan areas, South Korea. METHODS: A cross-sectional study through an online survey. RESULTS: Of participants, 62.7% had the intention to quit ECS-17.2% within one month, 14.0% within six months, and 31.5% when the time is right. Factors significantly associated with the intention to quit ECS were identified: "device type," "a shorter duration of ECS," and "having started ECS for quitting traditional cigarette smoking" at the intrapersonal-level; "negative attitudes of either peers or family members toward ECS" at the interpersonal-level; and "exposure to community smoking cessation educations" at the community-level. CONCLUSIONS: Approximately one-thirds of university e-cigarette users had no intention to quit ECS. The factors identified should be integrated into university level, behavioral smoking cessation strategies.

Effectiveness of a Mobile Health Management Program With a Challenge Strategy for Improving the Cardiovascular Health of Workers.

BACKGROUND: Workers' cardiovascular health can be influenced by individual willingness to practice healthy behaviors. A mobile health management program with a challenge strategy was administered to promote workers' healthy behaviors among small to medium-sized enterprises. METHODS: A 12-week program consisted of health communication with a challenge strategy was administered to the workers. RESULTS: The intervention group showed significantly improved scores for cardiovascular disease-related health behavior (Z = -2.44, P = 0.013), the job stress contributing factor of inadequate social support (F = 4.10, P = 0.049), and the cardiovascular disease-related health status of waist circumference (t = 3.22, P = 0.004), body fat (Z = -2.23, P = 0.024), and triglycerides (Z = -3.04, P = 0.001). CONCLUSION: This study's significance is its potential for increasing the convenience and joy of participating in intervention programs and acquiring health information through mobile platforms, which are easily accessible to the workers.

Perspectives on immune checkpoint ligands: expression, regulation, and clinical implications.

In the tumor microenvironment, immune checkpoint ligands (ICLs) must be expressed in order to trigger the inhibitory signal via immune checkpoint receptors (ICRs). Although ICL expression frequently occurs in a manner intrinsic to tumor cells, extrinsic factors derived from the tumor microenvironment can fine-tune ICL expression by tumor cells or prompt non-tumor cells, including immune cells. Considering the extensive interaction between T cells and other immune cells within the tumor microenvironment, ICL expression on immune cells can be as significant as that of ICLs on tumor cells in promoting antitumor immune responses. Here, we introduce various regulators known to induce or suppress ICL expression in either tumor cells or immune cells, and concise mechanisms relevant to their induction. Finally, we focus on the clinical significance of understanding the mechanisms of ICLs for an optimized immunotherapy for individual cancer patients. [BMB Reports 2021; 54(8): 403-412].

Job Stress and Cardiometabolic Lifestyle Modification Behaviors Among Workers in High-risk and Low-risk Workplaces.

OBJECTIVE: There is scarce evidence revealing an association between job stress and cardiometabolic lifestyle modification behaviors among workers. METHODS: A cross-sectional, correlation study was conducted among workers in high-risk and low-risk workplaces by work characteristics. RESULTS: Workers in high-risk workplaces had significantly higher job stress levels than low-risk workplaces. Higher job stress was significantly associated with lower cardiometabolic lifestyle modification behaviors (ß = -0.14, P = .001). This significant association was evident only for high-risk workplaces in total job stress (ß = -0.16, P = .001), including job demand (ß = -0.16, P = .005) and job insecurity (ß = -0.11, P = .026). CONCLUSIONS: Strategies for alleviating job stress should be prioritized to high-risk workplaces, and these efforts may concomitantly contribute to cardiometabolic risk reduction.

Enriching CCL3 in the Tumor Microenvironment Facilitates T cell Responses and Improves the Efficacy of Anti-PD-1 Therapy.

Chemokines are key factors that influence the migration and maintenance of relevant immune cells into an infected tissue or a tumor microenvironment. Therefore, it is believed that the controlled administration of chemokines in the tumor microenvironment may be an effective immunotherapy against cancer. Previous studies have shown that CCL3, also known as macrophage inflammatory protein 1-alpha, facilitates the recruitment of dendritic cells (DCs) for the presentation of tumor Ags and promotes T cell activation. Here, we investigated the role of CCL3 in regulating the tumor microenvironment using a syngeneic mouse tumor model. We observed that MC38 tumors overexpressing CCL3 (CCL3-OE) showed rapid regression compared with the wild type MC38 tumors. Additionally, these CCL3-OE tumors showed an increase in the proliferative and functional tumor-infiltrating T cells. Furthermore, PD-1 immune checkpoint blockade accelerated tumor regression in the CCL3-OE tumor microenvironment. Next, we generated a modified CCL3 protein for pre-clinical use by fusing recombinant CCL3 (rCCL3) with a non-cytolytic hybrid Fc (HyFc). Administering a controlled dose of rCCL3-HyFc via subcutaneous injections near tumors was effective in tumor regression and improved survival along with activated myeloid cells and augmented T cell responses. Furthermore, combination therapy of rCCL3-HyFc with PD-1 blockade exhibited prominent effect to tumor regression. Collectively, our findings demonstrate that appropriate concentrations of CCL3 in the tumor microenvironment would be an effective adjuvant to promote anti-tumor immune responses, and suggest that administering a long-lasting form of CCL3 in combination with PD-1 blockers can have clinical applications in cancer immunotherapy.