Isomerization Pathways of a Mismatched Base Pair of A:8OG in Free Duplex DNA.

The A:8OG base pair (bp) is the outcome of DNA replication of the mismatched C:8OG bp. A high A:8OG bp population increases the C/G to A/T transversion mutation, which is responsible for various diseases. MutY is an important enzyme in the error-proof cycle and reverts A:8OG to C:8OG bp by cleaving adenine from the A:8OG bp. Several X-ray crystallography studies have determined the structure of MutY during the lesion scanning and lesion recognition stages. Interestingly, glycosidic bond (χ) angles of A:8OG bp in those two lesion recognition structures were found to differ, which implies that χ-torsion isomerization should occur during the lesion recognition process. In this study, as a first step to understanding this isomerization process, we characterized the intrinsic dynamic features of A:8OG in free DNAs by a free energy landscape simulation at the all-atom level. In this study, four isomerization states were assigned in the order of abundance: Aanti:8OGsyn > Aanti:8OGanti > Asyn:8OGanti ≈ Asyn:8OGsyn. Of these bp states, only 8OG in Asyn:8OGanti was located in the extrahelical space, whereas the purine bases (A and 8OG) in the other bp states remained inside the DNA helix. Also, free energy landscapes showed that the isomerization processes connecting these four bp states proceeded mostly in the intrahelical space via successive single glycosidic bond rotations of either A or 8OG.

Three-State Diffusion Model of DNA Glycosylase Translocation along Stretched DNA as Revealed by Free Energy Landscapes at the All-Atom Level.

DNA glycosylases play key roles in the maintenance of genomic integrity. These enzymes effectively find rare damaged sites in DNA and participate in subsequent base excision repair. Single-molecule and ensemble experiments have revealed key aspects of this damage-site searching mechanism and the involvement of facilitated diffusion. In this study, we describe free energy landscapes of enzyme translocation along nonspecific DNA obtained using a fully atomistic molecular dynamics (MD) simulation of a well-known DNA glycosylase, human 8-oxoguanine DNA glycosylase 1 (hOGG1). Based on an analysis of simulated free energy profiles, we propose a three-state model for the damage-site searching mechanism. In the three states, named the L1, L2, and L3 states, the L1 state is a helical sliding mode in close contact with DNA, whereas the L2 state is a major- or minor-groove tracking mode in loose contact with DNA and the L3 state is a two-dimensional freely diffusing mode during which hOGG1 is somewhat removed from the DNA surface (∼24 Šaway from the surface). This three-state model well describes key experimental findings obtained from single-molecule and ensemble experiments and provides a unified molecular picture of the DNA lesion-searching mechanism of hOGG1.

Upregulation of human GD3 synthase (hST8Sia I) gene expression during serum starvation-induced osteoblastic differentiation of MG-63 cells.

In this study, we have firstly elucidated that serum starvation augmented the levels of human GD3 synthase (hST8Sia I) gene and ganglioside GD3 expression as well as bone morphogenic protein-2 and osteocalcin expression during MG-63 cell differentiation using RT-PCR, qPCR, Western blot and immunofluorescence microscopy. To evaluate upregulation of hST8Sia I gene during MG-63 cell differentiation by serum starvation, promoter area of the hST8Sia I gene was functionally analyzed. Promoter analysis using luciferase reporter assay system harboring various constructs of the hST8Sia I gene proved that the cis-acting region at -1146/-646, which includes binding sites of the known transcription factors AP-1, CREB, c-Ets-1 and NF-κB, displays the highest level of promoter activity in response to serum starvation in MG-63 cells. The -731/-722 region, which contains the NF-κB binding site, was proved to be essential for expression of the hST8Sia I gene by serum starvation in MG-63 cells by site-directed mutagenesis, NF-κB inhibition, and chromatin immunoprecipitation (ChIP) assay. Knockdown of hST8Sia I using shRNA suggested that expressions of hST8Sia I and GD3 have no apparent effect on differentiation of MG-63 cells. Moreover, the transcriptional activation of hST8Sia I gene by serum starvation was strongly hindered by SB203580, a p38MAPK inhibitor in MG-63 cells. From these results, it has been suggested that transcription activity of hST8Sia I gene by serum starvation in human osteosarcoma MG-63 cells is regulated by p38MAPK/NF-κB signaling pathway.

Association between Occupational Noise Exposure and Insomnia among Night-Shift Production Workers: A 4-Year Follow-up Study.

Objectives: This study aimed to investigate whether occupational noise exposure is a risk factor for insomnia among male night-shift production workers. Methods: This study followed 623 male night-shift production workers at a tire manufacturing factory without insomnia for 4 years. Insomnia was evaluated based on the insomnia severity index at baseline and at 4-year follow-up. A score of ≥15 was defined as insomnia. The higher occupational noise exposure group was defined as those individuals exposed to 8-hour time-weighted-average noise above 80 dB (A). Results: Participants' mean age was 46.3 ± 5.6 years. Of the 623 participants, 362 (58.1%) were in the higher occupational noise exposure group. At 4-year follow-up, insomnia occurred in 3.2% (n = 20) of the participants. In a multiple logistic regression analysis, the odds ratio of insomnia was 3.36 (95% confidence interval 1.083-10.405, P = 0.036) in the higher occupational noise exposure group when compared with the lower noise exposure group after adjusting for confounders. Conclusion: Our findings suggested that occupational noise exposure affected insomnia in male night-shift production workers. To prevent insomnia, efforts are required to reduce workplace noise exposure levels. Alternatively, moving to a less noisy work environment should be considered for workers with severe insomnia.

Computational Probing of the Folding Mechanism of Human Telomeric G-Quadruplex DNA.

The human telomeric (htel) sequences in the terminal regions of human telomeres form diverse G-quadruplex (GQ) structures. Despite much experimental efforts to elucidate the folding pathways of htel GQ, no comprehensive model of htel GQ folding has been presented. Here, we describe folding pathways of the htel GQ determined by state-of-the-art enhanced sampling molecular dynamics simulation at the all-atom level. Briefly, GQ folding is initiated by the formation of a single-hairpin and then followed by the formation of double-hairpins, which then branch via distinct folding pathways to produce different GQ topologies (antiparallel chair, antiparallel basket, hybrids 1 and 2, and parallel propeller). In addition to these double-hairpin states, three-triad and two-tetrad structures in antiparallel backbone alignment serve as key intermediates that connect the GQ folding and transition between two different GQs.

Validation of prediction algorithm for risk estimation of intracranial aneurysm development using real-world data.

Intracranial aneurysm (IA) is difficult to detect, and most patients remain undiagnosed, as screening tests have potential risks and high costs. Thus, it is important to develop risk assessment system for efficient and safe screening strategy. Through previously published research, we have developed a prediction model for the incidence risk of IA using cohort observational data. This study was designed to verify whether such a prediction model also demonstrates sufficient clinical performance in predicting the prevalence risk at the point of health screening, using cross-sectional data. The study population comprised individuals who visited the Chonnam National University Hwasun Hospital Health Promotion Center in Korea for voluntary medical checkups between 2007 and 2019. All participants had no history of cerebrovascular disease and underwent brain CTA for screening purpose. Presence of IA was evaluated by two specialized radiologists. The risk score was calculated using the previously developed AI model, and 0 point represents the lowest risk and 100 point represents the highest risk. To compare the prevalence according to the risk, age-sex standardization using national database was performed. A study collected data from 5942 health examinations, including brain CTA data, with participants ranging from 20 to 87 years old and a mean age of 52 years. The age-sex standardized prevalence of IA was 3.20%. The prevalence in each risk group was 0.18% (lowest risk, 0-19), 2.12% (lower risk, 20-39), 2.37% (mid-risk, 40-59), 4.00% (higher risk, 60-79), and 6.44% (highest risk, 80-100). The odds ratio between the lowest and highest risk groups was 38.50. The adjusted proportions of IA patients in the higher and highest risk groups were 26.7% and 44.5%, respectively. The median risk scores among IA patients and normal participants were 74 and 54, respectively. The optimal cut-off risk score was 60.5 with an area under the curve of 0.70. We have confirmed that the incidence risk prediction model built through machine learning also shows viable clinical performance in predicting prevalence risk. By utilizing this prediction system, we can effectively predict not only the incidence risk but also the prevalence risk, which is the probability of already having the disease, using health screening data. This may enable us to consider strategies for the early detection of intracranial aneurysms.

A case of syncope in a villager with hypertrophic cardiomyopathy after hydrogen sulfide exposure by an unauthorized discharge of wastewater.

Background: Hydrogen sulfide is a toxic substance that humans can be exposed to occupationally, and cases of hydrogen sulfide poisoning of workers in industrial sites are commonly reported. However, there have been no cases of poisoning of the public due to an unauthorized discharge of wastewater, so it is important to describe this incident. Case presentation: In a small village in Jeollanam-do, Republic of Korea, accounts of a terrible stench had been reported. A 26-year-old man who lived and worked in a foul-smelling area was taken to the emergency room with a headache, dizziness, nausea, and repeated syncope. A subsequent police and Ministry of Environment investigation determined that the cause of the stench was the unauthorized discharge of 9 tons of wastewater containing hydrogen sulfide through a stormwater pipe while the villagers were sleeping. The patient had no previous medical history or experience of symptoms. Leukocytes and cardiac markers were elevated, an electrocardiogram indicated biatrial enlargement, left ventricular hypertrophy, and corrected QT interval prolongation. Myocardial hypertrophy was detected on a chest computed tomography scan, and hypertrophic cardiomyopathy was confirmed on echocardiography. After hospitalization, cardiac marker concentrations declined, symptoms improved, and the patient was discharged after 7 days of hospitalization. There was no recurrence of symptoms after discharge. Conclusions: We suspect that previously unrecognized heart disease manifested or was aggravated in this patient due to exposure to hydrogen sulfide. Attention should be paid to the possibility of unauthorized discharge of hydrogen sulfide, etc., in occasional local incidents and damage to public health. In the event of such an accident, it is necessary to have government guidelines in place to investigate health impact and follow-up clinical management of exposed residents.

The Association Between Blood Lead Levels and Coronary Artery Calcium Score Determined by Using Coronary Computed Tomography Angiography.

BACKGROUND: Lead exposure is a known risk factor for cardiovascular disease (CVD), and coronary artery calcification (CAC) is a biomarker for diagnosing atherosclerotic CVD. This study investigated the association between blood lead level (BLL) and CAC using coronary computed tomography (CT) angiography. METHODS: This study enrolled 2,189 participants from the general population with no history or symptoms of CVD. All participants underwent coronary CT angiography, health examination, and BLL testing. The association between coronary artery calcium score (CACS) and BLL was analyzed. RESULTS: The arithmetic mean of BLL was 2.71 ± 1.26 µg/dL, and the geometric mean was 2.42 (1.64) µg/dL, ranging from 0.12 to 10.14 µg/dL. There was a statistically significant positive correlation between CACS and BLL (r = 0.073, P < 0.001). Mean BLLs among predefined CACS categories were as follows: absent grade (CACS = 0), 2.67 ± 1.23 µg/dL; minimal grade (> 0, < 10), 2.81 ± 1.25 µg/dL; mild grade (≥ 10, < 100), 2.74 ± 1.29 µg/dL; moderate grade (≥ 100, < 400), 2.88 ± 1.38 µg/dL; severe grade (≥ 400): 3.22 ± 1.68 µg/dL. The odds ratio for severe CAC was 1.242 in association with an 1 µg/dL increase in BLL (P = 0.042). CONCLUSION: Using coronary CT angiography, we determined a positive correlation between BLL and CAC among participants without CVD from the general population. To reduce the burden of CVD, efforts and policies should be geared toward minimizing environmental lead exposure.

Cancer Incidence in Korean Healthcare Workers in Hospitals.

OBJECTIVES: Healthcare workers in hospitals (HHCWs), a notably increasing workforce, face various occupational hazards. A high incidence of cancer among HHCWs has been observed; however, the cancer incidence status among HHCWs in South Korea is yet to be studied. This study aimed to assess cancer incidence among HHCWs in South Korea. METHODS: We constructed a retrospective cohort of HHCWs using National Health Insurance claims data, including cancer incidence status and vital status, from 2007 to 2015. Those who had worked in hospitals for at least three years were defined as HHCWs. Standardized incidence ratios (SIRs) for all cancer types and standardized mortality ratios were calculated. RESULTS: A total of 107,646 HHCWs were followed up, and the total follow-up duration was 905,503 person-years. Compared to the total workers, female HHCWs showed significantly higher SIR for all cancers (observed cases = 1480; SIR = 1.25; 95% confidence interval [CI] = 1.06-1.47). The incidence of breast cancer among female HHCWs was significantly higher compared to that among total workers (observed cases = 376; SIR = 1.21; 95% CI = 1.09-1.36). CONCLUSIONS: Our findings indicate that female HHCWs have an elevated probability of developing cancer, which suggests that occupational risk factors such as night-shift work, anti-neoplastic medications, stressful jobs, and ionizing radiation should be assessed. Further investigation and occupational environment improvement activities are required.

Simple Ge/Si bilayer junction-based doping-less tunnel field-effect transistor.

Tunnel field-effect transistors (TFETs) have garnered great interest as an option for the replacement of metal-oxide-semiconductor field-effect transistors owing to their extremely low off-current and fast switching suitable for low-power-consumption applications. However, conventional doped TFETs have the disadvantage of introducing undesirable random dopant fluctuation (RDF) events, which cause a large variance in the threshold voltage and ambipolar leakage current at negative gate voltages. In this study, a simple approach for charge plasma-based doping-less TFETs (DL-TFETs), including the Ge/Si bilayer frame, which affects the RDF and low on-current issues, was developed by the commercially available Silvaco Atlas device simulator. The use of the Ge/Si bilayer enhances the on-current and point subthreshold swing to 1.4 × 10-6A and 16.6 mV dec-1, respectively. In addition, the dependencies of the Ge/Si junction boundary position and Ge content were examined systematically to attain a firm understanding of the electrical features in DL-TFETs.

Reduction in residual cyantraniliprole levels in spinach after various washing and blanching methods.

Pesticides are used to protect crops from pests and diseases. However, as many pesticides are toxic to humans, it is necessary to assess methods that can remove pesticide residues from agricultural products before human consumption. Spinach is consumed immediately after a relatively simple washing and heating process in the Republic of Korea. Cyantraniliprole is used as a systemic insecticide during spinach cultivation, which means it might remain in the crop after processing. Consequently, it is important to assess whether residues can be reduced to levels that are harmless to the human body after processing. This study investigated lowering the residual cyantraniliprole levels in spinach after washing and blanching. The amount of cyantraniliprole residue in the spinach samples sprayed with cyantraniliprole during cultivation was analyzed using ultrahigh-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). The time of each washing and blanching method was set at 1, 3, and 5 min. The residual levels of cyantraniliprole decreased by 15.1-54.6% and 60.1-93.5% based on the washing and blanching methods employed. The most effective washing method to lower residual cyantraniliprole levels was steeping with a neutral detergent, resulting in cyantraniliprole reduction by 42.9-54.6%. When spinach was blanched after steeping washing with a neutral detergent, the largest removal rates of 77.9 and 91.2% were observed after 1 and 3 min of blanching, respectively. Blanching for 5 min after steeping and running washing exhibited the highest reduction rate of 93.5%. Therefore, a considerable amount of cyantraniliprole residue in spinach could be removed by washing or blanching. Based on the results of this study, blanching after steeping washing can be implemented as an effective method of lowering pesticide concentrations in spinach and other crops, thereby reducing their potential toxicity to humans upon consumption.

Improving All-Atom Force Field to Accurately Describe DNA G-Quadruplex Loops.

The DNA G-quadruplex (GQ) displays structural polymorphisms, and interactions between its loops and flanking sequences critically determine which of the diverse GQ conformers is adopted. All-atom molecular dynamics (MD) simulations of GQs are computationally challenging due to slow folding times and force field (ff) artifacts. In an earlier study, a direct folding simulation of the simplest DNA GQ (TBA15) was first reported using a modified version of the AMBER bsc1 ff (bsc1_vdW ff). Despite this successful folding simulation, it was later found that the bsc1_vdW ff is somewhat limited in terms of describing loop structures of GQs, which is problematic because GQ loop regions play key roles in ligand binding to modulate GQ activities. In this study, we further modified the bsc1_vdW ff to enhance the GQ loop prediction by fine-tuning a limited number of van der Waals (vdW) parameters of the standard AMBER bsc1 ff to improve the GQ loop distribution of a target GQ system (three-layered antiparallel GQ; mHtel21). Test simulations of this newly generated ff (bsc1_vdWL ff) on DNA GQs with diverse topologies (hybrid1, hybrid2, and parallel propeller) revealed that loop structures were predicted more accurately than by the bsc1_vdW ff. We consider that enhanced sampling MD simulation methods in combination with bsc1_vdWL provide useful simulation protocols for resolving outstanding issues of DNA GQ folding and GQ/ligand binding at the all-atom level.

Low QRS Voltage in Limb Leads Indicates Accompanying Precordial Voltage Attenuation Resulting in Underestimation of Left Ventricular Hypertrophy.

Low QRS voltage (LQRSV) in electrocardiography (ECG) often occurs in limb leads without apparent cause. However, its clinical significance is obscure in healthy populations. We reviewed patients aged over 60 who were scheduled for non-cardiac surgery in two hospitals. Patients underwent pre-operative ECG, echocardiography, pulmonary function test, and chest X-ray. Patients with LQRSV isolated to limb leads and patients without LQRSV were selected from separate hospitals. Among the 9832 patients screened in one hospital, 292 (3.0%) showed LQRSV in limb leads. One-hundred and ninety-four without LQRSV were selected as the control from the 216 patients screened at the other hospital. For primary analysis, patients with structural heart disease or classic etiologies of LQRSV were excluded. Patients with LQRSV had a higher proportion of male and a greater body mass index. Precordial QRS voltages were smaller, whereas left ventricular mass index and the prevalence of echocardiographic left ventricular hypertrophy (LVH) was higher in patients with LQRSV than in those without. Consequentially, diagnostic performance of precordial voltage criteria for LVH was particularly poor in patients with LQRSV in limb leads. LQRSV in limb leads frequently occurs without apparent etiologies. ECG voltage criteria may underestimate LVH in a relatively healthy population with LQRSV in limb leads.

Seroprevalence of measles, mumps, rubella, and varicella-zoster antibodies in new female nurses in the Republic of Korea.

BACKGROUND: For health care workers, immune management plays an important role in the protection against infectious diseases. This study investigated the seroprevalence of measles, mumps, rubella, and varicella-zoster in newly employed female nurses. METHODS: We conducted a survey on the seroprevalence of measles, mumps, rubella, and varicella-zoster in newly employed female nurses at a university hospital from 2011 to 2019, before the nurses were given their department placements and duty start. Enzyme-linked immunosorbent and chemiluminescence immunoassays were used to detect immunoglobulin G antibodies. We analyzed whether there was a significant difference in seroprevalence depending on the age, birth year, birth season, and region of residence (metropolitan residency: yes or no). RESULTS: The arithmetic mean ages of the participants were 28.6 ± 4.8, 23.5 ± 3.2, 23.6 ± 3.0, and 26.1 ± 4.5 years for measles, mumps, rubella, and varicella-zoster, respectively. The seropositivity rates were 93.9% (551/587), 60.2% (50/83), 83.3% (3,093/3,711), and 89.5% (978/1,093) for measles, mumps, rubella, and varicella-zoster, respectively. Significant differences in the seroprevalence when assessed according to the age and birth year were noted with measles, while significant differences in the seroprevalence were only noted with rubella and varicella-zoster when assessed according to birth year and age, respectively. CONCLUSIONS: In this study, we identified the levels of antibody prevalence in new female nurses. Considering the seropositivity levels, cost-effectiveness, and convenience for the participants, we recommend that the measles-mumps-rubella vaccination be provided without serologic testing for all new female nurses and the varicella-zoster vaccination only be performed for persons who are negative after serologic testing. And it would be useful if the vaccinations were combined with compulsory worker health examinations, such as the pre-placement health examinations.

The relationship between chronotypes and musculoskeletal problems in male automobile manufacturing workers.

BACKGROUND: Previous studies have shown that morning types are less sensitive to pain. This study aimed to examine the relationship between chronotypes and musculoskeletal problems in workers with musculoskeletal burdens at work. METHODS: This cross-sectional study included 119 male production workers from a large automobile manufacturing plant. All the participants worked 2 shifts and worked on the automobile assembly line. Data were obtained using structured questionnaires, including the reduced Morningness-Eveningness Questionnaire (rMEQ), and musculoskeletal symptom questionnaire. Participants with an rMEQ score of 18 points or more were defined as morning-type workers (MTWs). Participants whose scores were less than 18 points were defined as neither-type workers (NTWs). RESULTS: The arithmetic mean age was 51.8 ± 5.3 years. MTWs and NTWs accounted for 35.3% and 64.7% of the total participants, respectively. Evening- and intermediate-type workers accounted form 6.7% and 58.0% of the participants, respectively. There was no significant difference in the health indicators when the MTW and NTW groups were compared. However, the musculoskeletal symptom questionnaire demonstrated a significant difference between the MTW and NTW groups. In the preceding year, the MTW group had significantly lower musculoskeletal pain and treatment ratios compared to the NTW group (35.7% vs. 62.3%, p = 0.005 and 14.3% vs. 32.5%, p = 0.031, respectively). After adjusting for variables, the odds ratio (OR) for musculoskeletal pain was significantly higher in the NTW group than in the MTW group (OR, 3.112; 95% confidence interval, 1.285-7.535; p = 0.012). CONCLUSIONS: In this study, the musculoskeletal pain ratio was significantly lower for MTWs when compared to NTWs. Chronotypes could play an important role in work-related musculoskeletal disorders. Further, larger-scale, follow-up studies on chronotypes are required to assist in the prevention of musculoskeletal disorders in future.

Free-Energy Landscape of a pH-Modulated G·C Base Pair Transition from Watson-Crick to Hoogsteen State in Duplex DNA.

In double-helical DNAs, the most stable Watson-Crick (WC) base pair (bp) can be in thermal equilibrium with much less abundant Hoogsteen (HG) bp by the spontaneous rotation of the glycosidic angle in purine bases. Previous experimental studies showed that in the case of a G·C bp, the population of the transient HG is enhanced as a protonated form (HG+) through the protonation of the cytosine base under weakly acidic conditions. Hence, pH is a key factor that can modulate this transition event from the WC to HG+ bp. In this study, to computationally probe the overall free-energy landscapes of this pH-modulated G·C HG breathing, a comprehensive classical molecular dynamics (MD) simulation protocol is proposed using an enhanced sampling MD in conjunction with the standard thermodynamic integration method. From this MD protocol proposed, the free-energy surfaces of the G·C bp transition from the WC to HG bp were constructed successfully at any pH range, producing pH-dependent free-energy quantities in close agreement with previously reported experimental results. The simulation protocol is expected to provide valuable atomistic insight into the DNA bp transition events coupled with protonation or tautomeric shift in a target bp.

Development of Lidocaine-Loaded Dissolving Microneedle for Rapid and Efficient Local Anesthesia.

Lidocaine is a local anesthetic agent used in the form of injection and topical cream. However, these formulation types have limitations of being either painful or slow-acting, thereby hindering effective and complete clinical performance of lidocaine. Dissolving microneedles (DMNs) are used to overcome these limitations owing to their fast onset time and minimally invasive administration methods. Using hyaluronic acid and lidocaine to produce the drug solution, a lidocaine HCl encapsulated DMN (Li-DMN) was fabricated by centrifugal lithography. The drug delivery rate and local anesthetic quality of Li-DMNs were evaluated using the pig cadaver insertion test and Von Frey behavior test. Results showed that Li-DMNs could deliver sufficient lidocaine for anesthesia that is required to be utilized for clinical level. Results from the von Frey test showed that the anesthetic effect of Li-DMNs was observed within 10 min after administration, thus confirming fast onset time. A toxicity test for appropriate clinical application standard was conducted with a microbial limit test and an animal skin irritation test, showing absence of skin irritation and irritation-related microorganisms. Overall, Li-DMN is a possible alternative drug delivery method for local anesthesia, meeting the requirements for clinical conditions and overcoming the drawbacks of other conventional lidocaine administration methods.

Regulation of human ß-galactoside α2,6-sialyltransferase (hST6Gal I) gene expression during differentiation of human osteoblastic MG-63 cells.

In this study, we found that gene expression of the human ß-galactoside α2,6-sialyltransferase (hST6Gal I) was specifically increased during differentiation of human MG-63 osteoblastic cells by serum starvation (SS). In parallel, a distinct increase in binding to SNA, the α2,6-sialyl-specific lectin, was observed in serum-starved cells, as demonstrated by FACS analysis. 5'-Rapid amplification of cDNA ends analysis demonstrated that the increase of hST6Gal I transcript by SS is mediated by P1 promoter. To elucidate transcriptional regulation of hST6Gal I in SS-induced MG-63 cells, we functionally characterized the P1 promoter region of the hST6Gal I gene. The 5'-deletion analysis of P1 promoter region revealed that the 189 bp upstream region of transcription start site is critical for transcriptional activity of hST6Gal I gene in SS-induced MG-63 cells. This region contains the predicted binding sites for several transcription factors, including AREB6, FOXP1, SIX3, HNF1, YY2, and MOK2. The mutagenesis analysis for these sites and chromatin immunoprecipitation assay demonstrated that the YY2 binding site at -98 to -77 was essential for the SS-induced hST6Gal I gene expression during differentiation of MG-63 cells.

Rapidly Separable Micropillar Integrated Dissolving Microneedles.

Dissolving microneedle (DMN) patches were developed as efficient and patient-friendly transdermal delivery systems for biopharmaceuticals. However, recent studies have confirmed that the efficiency of DMNs to deliver biopharmaceuticals is highly reduced because of incomplete insertion caused by the stiffness and elastic properties of the skin. Therefore, micropillar integrated DMNs were developed to overcome the insertion limitations of DMN patches. Although micropillars were designed as integrated applicators to implant DMNs across the skin, they can also become inserted into the skin, leading to skin injury and inflammation. Herein, we have developed a separable micropillar integrated DMN (SPDMN) capable of inserting DMNs across the skin with high efficiency while minimizing skin injury risk through the introduction of a safety ring feature. Unlike previously developed systems, the SPDMN does not require continuous skin attachment and can be detached immediately post-application, leaving DMNs implanted inside the skin. Altogether, the findings of this study lead to the development of a quick, safe, and efficient DMN-based drug delivery platform.

Improving Temperature Generator in Parallel Tempering Simulation in the NPT Condition.

Parallel tempering (PT) simulations provide a powerful computational tool to accelerate conformational searches of complex molecular systems. In this method, multiple replica systems assigned to different temperatures run in parallel and undergo tandem replica exchange events to enhance conformational mixing in temperature space. Efficient PT simulations require a uniform acceptance ratio across all the replicas. In the context of a previous energy distribution-based temperature generation (TG) scheme, we propose an improved TG protocol to maintain such a uniform exchange probability in general PT simulations.