STK19 facilitates the clearance of lesion-stalled RNAPII during transcription-coupled DNA repair.

Transcription-coupled DNA repair (TCR) removes bulky DNA lesions impeding RNA polymerase II (RNAPII) transcription. Recent studies have outlined the stepwise assembly of TCR factors CSB, CSA, UVSSA, and TFIIH around lesion-stalled RNAPII. However, the mechanism and factors required for the transition to downstream repair steps, including RNAPII removal to provide repair proteins access to the DNA lesion, remain unclear. Here, we identify STK19 as a new TCR factor facilitating this transition. Loss of STK19 does not impact initial TCR complex assembly or RNAPII ubiquitylation but delays lesion-stalled RNAPII clearance, thereby interfering with the downstream repair reaction. Cryo-EM and mutational analysis reveal that STK19 associates with the TCR complex, positioning itself between RNAPII, UVSSA, and CSA. The structural insights and molecular modeling suggest that STK19 positions the ATPase subunits of TFIIH onto DNA in front of RNAPII. Together, these findings provide new insights into the factors and mechanisms required for TCR.

Identification of High Linoleic Acid Varieties in Tetraploid Perilla Through Gamma-ray Irradiation and CRISPR/Cas9.

Perilla (Perilla frutescens (L.) var frutescens) is a traditional oil crop in Asia, recognized for its seeds abundant in α-linolenic acid (18:3), a key omega-3 fatty acid known for its health benefits. Despite the known nutritional value, the reason behind the higher 18:3 content in tetraploid perilla seeds remained unexplored. Gamma irradiation yielded mutants with altered seed fatty acid composition. Among the mutants, DY-46-5 showed a 27% increase in 18:2 due to the 4 bp deletion of PfrFAD3b and NC-65-12 displayed a 16% increase in 18:2 due to the loss of function of PfrFAD3a through a large deletion. Simultaneous knockout of two copies of FATTY ACID DESATURASE 3 (PfrFAD3a and PfrFAD3b) using CRISPR/Cas9 resulted in an increase in 18:2 by up to 75% and a decrease in 18:3 to as low as 0.3% in seeds, emphasizing the pivotal roles of both genes in 18:3 synthesis in tetraploid perilla. Furthermore, diploid Perilla citriodora, the progenitor of cultivated tetraploid perilla, harbors only PfrFAD3b, with fatty acid analysis revealing lower 18:3 levels than tetraploid perilla. In conclusion, the enhanced 18:3 content in cultivated tetraploid perilla seeds can be attributed to the acquisition of two FAD3 copies through hybridization with wild-type diploid perilla.

Mortality trends in people with disabilities before and during the COVID-19 pandemic in South Korea, 2017-2022.

Objective: To investigate temporal trends in mortality rates and underlying causes of death in persons with disabilities before and during the coronavirus disease 2019 (COVID-19) pandemic. Methods: Annual mortality rates and causes of death were analyzed using data covering the 2017-2022 period. Results: The mortality rate among people with disabilities increased from 2017 to 2022; the rate was five times higher during COVID-19 in this population than in the general population. When analyzing the cause of death, the incidence of infectious diseases and tuberculosis decreased after COVID-19. In contrast, the incidence of other bacillary disorders (A30-A49) increased. The incidence of respiratory system diseases (J00-J99), influenza and pneumonia (J09-J18), and other acute lower respiratory infections (J20-J22) decreased before COVID-19, while the incidence of lung diseases due to external agents (J60-J70), other respiratory diseases principally affecting the interstitium (J80-J84), and other diseases of the pleura (J90-J94) increased during the pandemic. The risk of COVID-19 death among people with disabilities was 1.1-fold higher for female patients (95% CI = 1.06-1.142), 1.41-fold for patients aged 70 years and older (95% CI = 1.09-1.82), and 1.24-fold higher for people with severe disabilities (95% CI = 1.19-1.28). Conclusions: The mortality rate in people with disabilities significantly increased during COVID-19, compared with that before the pandemic. People with disabilities had a higher mortality rate during COVID-19 compared with the general population. Risk factors must be reduced to prevent high mortality rates in this population.

Predicting treatment outcomes in patients with panic disorder: Cross-sectional and two-year longitudinal structural connectome analysis using machine learning methods.

PURPOSE: This study examined the relationship between structural brain networks and long-term treatment outcomes in patients with panic disorder (PD) using machine learning methods. METHOD: The study involved 80 participants (53 PD patients and 27 healthy controls) and included clinical assessments and MRI scans at baseline and after two years (160 MRIs). Patients were categorized based on their response to two-year pharmacotherapy. Brain networks were analyzed using white matter tractography and network-based statistics. RESULTS: Results showed structural network changes in PD patients, particularly in the extended fear network, including frontal regions, thalamus, and cingulate gyrus. Longitudinal analysis revealed that increased connections to the amygdala, hippocampus, and insula were associated with better treatment response. Conversely, overconnectivity in the amygdala and insula at baseline was associated with poor response, and similar patterns were found in the insula and parieto-occipital cortex related to non-remission. This study found that SVM and CPM could effectively predict treatment outcomes based on network pattern changes in PD. CONCLUSIONS: These findings suggest that monitoring structural connectome changes in limbic and paralimbic regions is critical for understanding PD and tailoring treatment. The study highlights the potential of using personalized biomarkers to develop individualized treatment strategies for PD.

A Rare Case of Intracranial Growing Teratoma Syndrome in a Young Adult.

Intracranial growing teratoma syndrome (iGTS) is a rare phenomenon in patients with non-germinomatous germ cell tumor (NGGCT) after chemotherapy or radiotherapy. It manifests as paradoxical growth of teratomatous components, with multiple cystic lesions on cranial imaging despite normalized tumor markers. This paper presents a 22-year-old male with iGTS, diagnosed one month after chemotherapy against NGGCT. Initially diagnosed with presumptive pineal NGGCT causing obstructive hydrocephalus, the patient underwent endoscopic third ventriculostomy and extraventricular drainage with tumor biopsy followed by two chemotherapy cycles. Despite normalization of tumor markers, follow-up MRI showed increased tumor size with honeycomb-like cystic patterns. The patient underwent suboccipital craniotomy for tumor removal via combined telovelar and infratentorial supracerebellar approaches. The final pathology confirmed mature teratoma. However, postoperative bleeding and left thalamic infarction occurred, resulting in severe neurological deficits. Despite challenges, the patient eventually regained the ability to follow simple commands. To understand iGTS pathophysiology, several hypotheses, including the differentiation of immature components and the uninhibited growth of mature components induced by chemotherapy or radiotherapy, were explored. Surgical intervention remains as an ideal treatment, while clinical trials investigate chemotherapy options. Frequent imaging follow-ups are crucial for early detection in iGTS for NGGCT patients.

Assessing the abundance, sources, and potential ecological risk assessment of microplastics using their particle and mass units in Uiam Lake, South Korea.

Microplastics (MPs) enter lakes through various pathways, including effluents from wastewater treatment plants (WWTPs), surface runoff, and improperly disposed of plastic waste. In this study, the extent of MPs pollution in Uiam Lake in fall of 2022 and spring of 2023 was assessed by determining both the number (n/m3) and mass concentrations (µg/m3) of MPs. Moreover, the correlation between water quality parameters and MP properties was analyzed, and an ecological risk assessment was conducted. MPs abundance was higher in spring than in fall, probably due to the lifting of coronavirus disease-19 restrictions, melting of ice, higher rainfall, and faster wind speed. Fragment was the dominant shape of the MPs collected, while polyvinyl chloride (PVC) and polyester/polyethylene terephthalate were the frequently detected polymer types of MPs in fall and spring, respectively. There was a moderate positive correlation between the number concentration of MPs and the total nitrogen, total phosphorus (T-P), and total organic carbon levels; in contrast, there was no significant relationship between the mass concentration of MPs and all water quality parameters. However, the abundance (µg/m3) of PVC and polymethyl methacrylate MPs were positively correlated with T-P and electrical conductivity. The pollution load index, polymer hazard index, and potential ecological risk index (PERI) were generally higher when the mass unit of MPs was used due to the presence of large-sized MPs composed of highly hazardous polymers (e.g., polyurethane, PVC, and alkyd). For instance, the PERI value of the WWTP effluent was at the very high level (>1200) in both seasons, regardless of the abundance unit of MPs. Therefore, WWTP effluents may have increased the ecological toxicity of MPs pollution in Uiam Lake.

Protective effect of Phyllostachys edulis (Carrière) J. Houz against chronic ethanol-induced cognitive impairment in vivo.

BACKGROUND/OBJECTIVES: Chronic alcohol consumption causes oxidative stress in the body, which may accumulate excessively and cause a decline in memory; problem-solving, learning, and exercise abilities; and permanent damage to brain structure and function. Consequently, chronic alcohol consumption can cause alcohol-related diseases. MATERIALS/METHODS: In this study, the protective effects of Phyllostachys edulis (Carrière) J. Houz (PE) against alcohol-induced neuroinflammation and cognitive impairment were evaluated using a mouse model. Alcohol (16%, 5 g/kg/day for 6 weeks) and PE (100, 250, and 500 mg/kg/day for 21 days) were administered intragastrically to mice. RESULTS: PE showed a protective effect against memory deficits and cognitive dysfunction caused by alcohol consumption, confirmed through behavioral tests such as the T-maze, object recognition, and Morris water maze tests. Additionally, PE attenuated oxidative stress by reducing lipid oxidation, nitric oxide, and reactive oxygen species levels in the mice's brains, livers, and kidneys. Improvement of neurotrophic factors and downregulation of apoptosis-related proteins were confirmed in the brains of mice fed low and medium concentrations of PE. Additionally, expression of antioxidant enzyme-related proteins GPx-1 and SOD-1 was enhanced in the liver of PE-treated mice, related to their inhibitory effect on oxidative stress. CONCLUSION: This suggests that PE has both neuroregenerative and antioxidant effects. Collectively, these behavioral and histological results confirmed that PE could improve alcohol-induced cognitive deficits through brain neurotrophic and apoptosis protection and modulation of oxidative stress.

Elevation of circulating neutrophil extracellular traps in endometrial cancer: Poor prognostic value of cell-free double-stranded DNA.

OBJECTIVE: Neutrophils produce neutrophil extracellular traps (NETs) by releasing nuclear contents into the extracellular environment. NETs are associated with systemic inflammation and cancer development and progression. We aimed to investigate whether NET markers are associated with the prognosis of endometrial cancer. METHODS: Circulating levels of three NET markers (histone-DNA complex, cell-free double-stranded DNA (dsDNA), and neutrophil elastase) were measured in 98 patients with endometrial cancer who underwent surgery as primary treatment between January 2015 and June 2018 and 45 healthy women. Area under the receiver operating characteristic curve (AUC) analyses were conducted to investigate the diagnostic and prognostic utility of the markers for endometrial cancer. RESULTS: Patients with endometrial cancer showed significantly higher levels of the three NET markers than those in healthy controls. In discriminating endometrial cancer patients from healthy controls, the three NET markers showed AUC values in the following order: cell-free dsDNA (0.832; 95 % CI, 0.760-0.889), histone-DNA complex (0.740; 95 % CI, 0.660-0.809), and neutrophil elastase (0.689; 95 % CI, 0.607-0.764), comparable to those of CA-125 (0.741; 95 % CI, 0.659-0.813). Multivariate analysis adjusting for FIGO stage, histology, and lymphovascular space invasion, and lymph node involvement revealed that cell-free dsDNA level (cutoff: 95.2 ng/mL) was an independent prognostic marker for poor progression-free (adjusted HR, 2.75; 95 % CI, 1.096.92; P = 0.032) and overall survival (adjusted HR, 11.51; 95 % CI, 2.0664.22; P = 0.005) for patients with endometrial cancer. CONCLUSION: High levels of circulating NET markers were observed in patients with endometrial cancer. Cell-free dsDNA levels may play a role as prognostic markers for endometrial cancer.

Lactobacillus plantarum LPYC225 mixture partially modulates the vaginal bacterial community of Gardnerella vaginalis-infected bacterial vaginosis in mice.

Bacterial vaginosis (BV) is defined as dysbiosis of the vaginal microbiome associated with the depletion of Lactobacilli and excessive growth of commensal or pathogenic bacteria. This study investigated the effects of lactic acid bacteria (LAB) mixture (LM; InoRexyne™) on the vaginal bacterial community of Gardnerella vaginalis (G. vaginalis)-infected BV mice. Single LAB and LM exhibited antibacterial and anti-inflammatory effects by inhibiting G. vaginalis growth and pro-inflammatory markers in RAW 264.7 cells. Administering LM did not significantly alter the vaginal architecture or fecal short-chain fatty acids but did significantly inhibit the vaginal interleukin-6 levels in the high LM group compared to the GV group. LM administration decreased the relative abundances of Enterobacter, Escherichia coli, and Bacteroides vulgatus in vaginal flushing fluids compared to the GV group. LM partially alleviated BV by inhibiting G. vaginalis growth and modulating the vaginal bacterial community, providing new insights into its modulatory effects on the vaginal microbiome in BV. Supplementary Information: The online version contains supplementary material available at 10.1007/s10068-024-01641-w.

Biological Effects of Double-Layered Hydroxyapatite and Zirconium Oxide Depositions on Titanium Surfaces.

Purpose: This study aimed to confirm the synergy effect of these two materials by evaluating osteoblast and antibacterial activity by applying a double-layered hydroxyapatite(HA) zirconium oxide(ZrO2) coating to titanium. Methods: The specimens used in this study were divided into four groups: a control group (polished titanium; group T) and three experimental groups: Group TH (RF magnetron sputtered HA deposited titanium), Group Z (ZrO2 ALD deposited titanium), and Group ZH (RF magnetron sputtered HA and ZrO2 ALD deposited titanium). The adhesion of Streptococcus mutans (S.mutans) to the surface was assessed using a crystal violet assay. The adhesion, proliferation, and differentiation of MC3T3-E1 cells, a mouse osteoblastic cell line, were assessed through a WST-8 assay and ALP assay. Results: Group Z showed a decrease in the adhesion of S. mutans (p < 0.05) and an improvement in osteoblastic viability (p < 0.0083). Group TH and ZH showed a decrease in adhesion of S. mutans (p < 0.05) and an increase in osteoblastic cell proliferation and cell differentiation (p < 0.0083). Group ZH exhibited the highest antibacterial and osteoblastic differentiation. Conclusion: In conclusion double-layered HA and ZrO2 deposited on titanium were shown to be more effective in inhibiting the adhesion of S. mutans, which induced biofilm formation, and increasing osteoblastic differentiation involved in osseointegration by the synergistic effect of the two materials.

Mucin-Rich Brain Metastasis May Show the T2-FLAIR Mismatch Sign: A Case Report and Literature Review.

This study describes a unique case of single mucin-rich brain metastasis in a patient with breast cancer, mimicking the T2-fluid attenuation inversion recovery (FLAIR) mismatch sign and masquerading as an isocitrate dehydrogenase-mutant astrocytoma. This case highlights the importance of considering mucin-rich lesions in the differential diagnosis of intracranial tumors exhibiting T2-FLAIR mismatch. Clinicians must recognize the potential convergence in imaging characteristics between these metastases and gliomas to guarantee prompt and accurate patient care.

Binding affinity screening of polyphenolic compounds in Stachys affinis extract (SAE) for their potential antioxidant and anti-inflammatory effects.

Free radical is a marker in various inflammatory diseases. The antioxidant effect protects us from this damage, which also plays an essential role in preventing inflammation. Inflammation protects the body from biological stimuli, and pro-inflammatory mediators are negatively affected in the immune system. Inflammation caused by LPS is an endotoxin found in the outer membrane of Gram-negative bacteria, which induces immune cells to produce inflammatory cytokines such as cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase. Based on this, the antioxidant and anti-inflammatory effects of plant extracts were investigated. First, the main phenolic compounds for the five peaks obtained from Stachys affinis extract (SAE) were identified. The antioxidant effect of each phenolic compound was confirmed through HPLC analysis before and after the competitive binding reaction between DPPH and the extract. Afterward, the anti-inflammatory effect of each phenolic compound was confirmed through competitive binding between COX2 and the extract in HPLC analysis. Lastly, the anti-inflammatory effect of SAE was confirmed through in vitro experiments and also confirmed in terms of structural binding through molecular docking. This study confirmed that phenolic compounds in SAE extract have potential antioxidant and anti-inflammatory effects, and may provide information for primary screening of medicinal plants.

Biomarkers of sleep-wake disturbance as predictors of cognitive decline and accelerated disease progression.

INTRODUCTION: In older adults, where sleep disturbances and cognitive impairment are common, mounting evidence suggests a potential connection between sleep and cognitive function, highlighting the significance of utilizing sleep as a biomarker for early detection of cognitive impairment to improve clinical outcomes in a noninvasive, cost-effective manner. AREAS COVERED: This review describes the relationship between sleep and cognitive function in older adults, encompassing both subjective and objective measures of sleep quality, duration, architecture, and sleep-disordered breathing. The authors consider the directionality of the associations observed in prospective and cross-sectional studies, exploring whether sleep disturbances precede cognitive decline or vice versa. Furthermore, they discuss the potential bidirectional relationships between sleep and Alzheimer's disease (AD) risks in older adults while also examining the neurodegenerative pathways of this relationship. EXPERT OPINION: Routine sleep monitoring in primary care settings has the potential to bolster early detection and treatment of sleep disturbance, and by extension, reduce the risk of dementia. Improving sleep assessment tools, such as wearables, provide scalable alternatives to traditional methods like polysomnography, potentially enabling widespread monitoring of sleep characteristics. Standardized measurement and inclusive participant recruitment are needed to enhance generalizability, while longitudinal studies are essential to understand the interaction between sleep and AD pathology.

Attenuation of esophageal anastomotic stricture through remote ischemic conditioning in a rat model.

Anastomotic stricture is a typical complication of esophageal atresia surgery. Remote ischemic conditioning (RIC) has demonstrated multiorgan benefits, however, its efficacy in the esophagus remains unclear. This study aimed to investigate whether applying RIC after esophageal resection and anastomosis in rats could attenuate esophageal stricture and improve inflammation. Sixty-five male Sprague-Dawley rats were categorized into the following groups: controls with no surgery, resection and anastomosis only, resection and anastomosis with RIC once, and resection and anastomosis with RIC twice. RIC included three cycles of hind-limb ischemia followed by reperfusion. Inflammatory markers associated with the interleukin 6/Janus kinase/ signal transducer and activator of transcription 3 (IL-6/JAK/STAT3) and tumor necrosis factor-alpha/nuclear factor-κB (TNF-α/NF-kB) signaling pathways were evaluated with RNA and protein works. The RIC groups showed significantly lower stricture rates, lower inflammatory markers levels than the resection and anastomosis-only group. The RIC groups had significantly lower IL-6 and TNFa levels than the resection and anastomosis-only group, confirming the inhibitory role of remote ischemic conditioning in the IL-6/JAK/STAT3 and TNF-α/NF-kB signaling pathways. RIC after esophageal resection and anastomosis can reduce the inflammatory response, improving strictures at the esophageal anastomosis site, to be a novel noninvasive intervention for reducing esophageal anastomotic strictures.

Double-Cannula Maneuver for the Double-Roll Configuration of Donor Descemet Membrane Outside Recipient Anterior Chamber During Descemet Membrane Endothelial Keratoplasty.

PURPOSE: The purpose of this study was to present a new surgical technique to convert a single roll of Descemet membrane (DM) into a double roll using 2 cannulas in a balanced salt solution-filled Petri dish during DM endothelial keratoplasty. METHODS: A single DM roll stained with trypan blue was placed in a balanced salt solution-filled Petri dish. Two cannulas (28G) were introduced from opposite ends of the single roll, inserted into the roll, and slowly spread apart to change the single roll into a double roll. The DM was aspirated into the modified Jones tube and loaded, maintaining a double-roll configuration with endothelium-down orientation in a bevel-up position. The modified Jones tube with the bevel down was inserted into the recipient anterior chamber through the main wound. The modified Jones tube was rotated to the bevel-up orientation. After checking the graft orientation, the DM was inserted into the recipient anterior chamber. The double-roll DM was easily unfolded by tapping the center of the cornea using a cannula. A 28G cannula was inserted under the DM, and the anterior chamber was filled with air. RESULTS: Three months after surgery, the patient's corrected visual acuity in the right eye was 6/7.5 and the endothelial cell count was 1095/mm2. The corneal thickness was 533 µm, and the cornea was clear. CONCLUSIONS: The double-cannula maneuver mechanically changes the single roll of the donor DM to a double roll outside the recipient anterior chamber, making DM unfolding easier and minimizing the risk of upside-down apposition of the donor DM.

Systemic Inflammatory Proteomic Biomarkers in Atopic Dermatitis: Exploring Potential Indicators for Disease Severity.

BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory cutaneous disorder, that emerges from intricate interplays among genetic predisposition, immune dysregulation, environmental factors, and compromised skin barrier. Understanding the inflammatory pathway in AD is important due to its fundamental role in the pathogenesis of AD. This study aimed to explore the diverse spectrum of proteins linked to the inflammation of AD and the relationship between systemic biomarkers and clinical severity in AD. METHODS: We examined the blood samples from 48 patients with AD and 48 healthy controls (HCs) using the Proximity Extension Assay (Olink). Differentially expressed proteins (DEPs) were identified and Pearson correlation analysis was conducted to determine systemic proteomic biomarkers associated with severity of AD. RESULTS: A total of 29 DEPs were significantly up-regulated and 2 DEPs were significantly down-regulated in AD compared with the HC. The MCP-4, IL-18, MCP-3, TNFRSF9, and IL-17C were the top 5 highest DEPs associated with the severity of AD. CONCLUSION: Our study sheds light on the intricate network of inflammatory proteins in AD and their potential implications for disease severity. Our results indicate that these systemic inflammatory proteins could be valuable for assessing AD severity and enhancing our understanding of the disease's complexity and its potential management strategies.

Dosimetric predictors of acute and late gastrointestinal toxicities in stereotactic online adaptive magnetic resonance-guided radiotherapy (SMART) for locally advanced pancreatic adenocarcinoma.

BACKGROUND AND PURPOSE: A retrospective evaluation of dosimetric predictors and leveraged dose-volume data for gastrointestinal (GI) toxicities for locally-advanced pancreatic cancer (LAPC) treated with daily stereotactic MRI-guided online-adaptive radiotherapy (SMART). MATERIALS AND METHODS: 147 patients with LAPC were treated with SMART at our institution between 2018 and 2021. Patients were evaluated using CTCAE V5.0 for RT-related acute (≤3 months) and late (>3 months) toxicities. Each organ at risk (OAR) was matched to a ≥ grade 2 (Gr2+) toxicity endpoint composite group. A least absolute shrinkage selector operator regression model was constructed by dose-volumes per OAR to account for OAR multicollinearity. A receiver operator curve (ROC) analysis was performed for the combined averages of significant toxicity groups to identify critical volumes per dose levels. RESULTS: 18 of 147 patients experienced Gr2+ GI toxicity. 17 Gr2+ duodenal toxicities were seen; the most significant predictor was a V33Gy odds ratio (OR) of 1.69 per cc (95 % CI 1.14-2.88). 17 Gr2+ small bowel (SB) toxicities were seen; the most significant predictor was a V33Gy OR of 1.60 per cc (95 % CI 1.01-2.53). The AUC was 0.72 for duodenum and SB. The optimal duodenal cut-point was 1.00 cc (true positive (TP): 17.8 %; true negative (TN); 94.9 %). The SB cut-point was 1.75 cc (TP: 16.7 %; TN: 94.3 %). No stomach or large bowel dose toxicity predictors were identified. CONCLUSIONS: For LAPC treated with SMART, the dose-volume threshold of V33Gy for duodenum and SB was associated with Gr2+ toxicities. These metrics can be utilized to guide future dose-volume constraints for patients undergoing upper abdominal SBRT.