Exploring the heart-brain and brain-heart axis: Insights from a bidirectional Mendelian randomization study on brain cortical structure and cardiovascular disease.

INTRODUCTION: The bidirectional relationship between the brain cortex and cardiovascular diseases (CVDs) remains inadequately explored. METHODS: This study employed bidirectional Mendelian randomization (MR) analysis to investigate the interaction between nine phenotypes, namely hypertension, heart failure, atrial fibrillation (AF), and coronary heart disease (CHD), and brain cortex measurements, including total surface area (SA), average thickness (TH), and the SA and TH of 34 regions based on the Desikan-Killiany atlas. The nine traits were obtained from sources such as the UK Biobank and FinnGen, etc., while MRI-derived traits of cortical structure were sourced from the ENIGMA Consortium. The primary estimate was obtained using the inverse-variance weighted approach. False discovery rate adjustment was applied to p-values (q-values) in the analyses for regional cortical structure. RESULTS: A total of 1260 two-sample MR analyses were conducted. Existing CHD demonstrated an influence on the SA of the banks of the superior temporal sulcus (bankssts) (q = 0.018) and the superior frontal lobe (q = 0.018), while hypertension was associated with changes in the TH of the lateral occipital region (q = 0.02). Regarding the effects of the brain cortex on CVD incidence, total SA was significantly associated with the risk of CHD. Additionally, 15 regions and four areas exhibited significant effects on blood pressure and AF risk, respectively (q < 0.05). These regions were primarily located in the frontal, temporal, and cingulate areas, which are responsible for cognitive function and mood regulation. CONCLUSION: The detection of cortical changes through MRI could aid in screening for potential neuropsychiatric disorders in individuals with established CVD. Moreover, abnormalities in cortical structure may predict future CVD risk, offering new insights for prevention and treatment strategies.

Protecting effects of 4-octyl itaconate on neonatal hypoxic-ischemic encephalopathy via Nrf2 pathway in astrocytes.

BACKGROUND: Neonatal hypoxic-ischemic encephalopathy (HIE) is one of the most common neurological problems occurring in the perinatal period. However, there still is not a promising approach to reduce long-term neurodevelopmental outcomes of HIE. Recently, itaconate has been found to exhibit anti-oxidative and anti-inflammatory effects. However, the therapeutic efficacy of itaconate in HIE remains inconclusive. Therefore, this study attempts to explore the pathophysiological mechanisms of oxidative stress and inflammatory responses in HIE as well as the potential therapeutic role of a derivative of itaconate, 4-octyl itaconate (4OI). METHODS: We used 7-day-old mice to induce hypoxic-ischemic (HI) model by right common carotid artery ligation followed by 1 h of hypoxia. Behavioral experiments including the Y-maze and novel object recognition test were performed on HI mice at P60 to evaluate long-term neurodevelopmental outcomes. We employed an approach combining non-targeted metabolomics with transcriptomics to screen alterations in metabolic profiles and gene expression in the hippocampal tissue of the mice at 8 h after hypoxia. Immunofluorescence staining and RT-PCR were used to evaluate the pathological changes in brain tissue cells and the expression of mRNA and proteins. 4OI was intraperitoneally injected into HI model mice to assess its anti-inflammatory and antioxidant effects. BV2 and C8D1A cells were cultured in vitro to study the effect of 4OI on the expression and nuclear translocation of Nrf2. We also used Nrf2-siRNA to further validate 4OI-induced Nrf2 pathway in astrocytes. RESULTS: We found that in the acute phase of HI, there was an accumulation of pyruvate and lactate in the hippocampal tissue, accompanied by oxidative stress and pro-inflammatory, as well as increased expression of antioxidative stress and anti-inflammatory genes. Treatment of 4OI could inhibit activation and proliferation of microglial cells and astrocytes, reduce neuronal death and relieve cognitive dysfunction in HI mice. Furthermore, 4OI enhanced nuclear factor erythroid-2-related factor (Nfe2l2; Nrf2) expression and nuclear translocation in astrocytes, reduced pro-inflammatory cytokine production, and increased antioxidant enzyme expression. CONCLUSION: Our study demonstrates that 4OI has a potential therapeutic effect on neuronal damage and cognitive deficits in HIE, potentially through the modulation of inflammation and oxidative stress pathways by Nrf2 in astrocytes.

Advancements and Challenges in the Integration of Indium Arsenide and Van der Waals Heterostructures.

The strategic integration of low-dimensional InAs-based materials and emerging van der Waals systems is advancing in various scientific fields, including electronics, optics, and magnetics. With their unique properties, these InAs-based van der Waals materials and devices promise further miniaturization of semiconductor devices in line with Moore's Law. However, progress in this area lags behind other 2D materials like graphene and boron nitride. Challenges include synthesizing pure crystalline phase InAs nanostructures and single-atomic-layer 2D InAs films, both vital for advanced van der Waals heterostructures. Also, diverse surface state effects on InAs-based van der Waals devices complicate their performance evaluation. This review discusses the experimental advances in the van der Waals epitaxy of InAs-based materials and the working principles of InAs-based van der Waals devices. Theoretical achievements in understanding and guiding the design of InAs-based van der Waals systems are highlighted. Focusing on advancing novel selective area growth and remote epitaxy, exploring multi-functional applications, and incorporating deep learning into first-principles calculations are proposed. These initiatives aim to overcome existing bottlenecks and accelerate transformative advancements in integrating InAs and van der Waals heterostructures.

Alternative splicing in parallel evolution and the evolutionary potential in sticklebacks.

Repeatability of adaptation to similar environments provides opportunity to evaluate the predictability of natural selection. While many studies have investigated gene expression differences between populations adapted to contrasting environments, the role of post-transcriptional processes such as alternative splicing has rarely been evaluated in the context of parallel adaptation. To address the aforementioned knowledge gap, we reanalysed transcriptomic data from three pairs of threespine stickleback (Gasterosteus aculeatus) ecotypes adapted to marine or freshwater environment. First, we identified genes with repeated expression or splicing divergence across ecotype pairs, and compared the genetic architecture and biological processes between parallelly expressed and parallelly spliced loci. Second, we analysed the extent to which parallel adaptation was reflected at gene expression and alternative splicing levels. Finally, we tested how the two axes of transcriptional variation differed in their potential for evolutionary change. Although both repeated differential splicing and differential expression across ecotype pairs showed tendency for parallel divergence, the degree of parallelism was lower for splicing than expression. Furthermore, parallel divergences in splicing and expression were likely to be associated with distinct cis-regulatory genetic variants and functionally unique set of genes. Finally, we found that parallelly spliced genes showed higher nucleotide diversity than parallelly expressed genes, indicating splicing is less susceptible to genetic variation erosion during parallel adaptation. Our results provide novel insight into the role of splicing in parallel adaptation, and underscore the contribution of splicing to the evolutionary potential of wild populations under environmental change.

A large language model-based generative natural language processing framework fine-tuned on clinical notes accurately extracts headache frequency from electronic health records.

OBJECTIVE: To develop a natural language processing (NLP) algorithm that can accurately extract headache frequency from free-text clinical notes. BACKGROUND: Headache frequency, defined as the number of days with any headache in a month (or 4 weeks), remains a key parameter in the evaluation of treatment response to migraine preventive medications. However, due to the variations and inconsistencies in documentation by clinicians, significant challenges exist to accurately extract headache frequency from the electronic health record (EHR) by traditional NLP algorithms. METHODS: This was a retrospective cross-sectional study with patients identified from two tertiary headache referral centers, Mayo Clinic Arizona and Mayo Clinic Rochester. All neurology consultation notes written by 15 specialized clinicians (11 headache specialists and 4 nurse practitioners) between 2012 and 2022 were extracted and 1915 notes were used for model fine-tuning (90%) and testing (10%). We employed four different NLP frameworks: (1) ClinicalBERT (Bidirectional Encoder Representations from Transformers) regression model, (2) Generative Pre-Trained Transformer-2 (GPT-2) Question Answering (QA) model zero-shot, (3) GPT-2 QA model few-shot training fine-tuned on clinical notes, and (4) GPT-2 generative model few-shot training fine-tuned on clinical notes to generate the answer by considering the context of included text. RESULTS: The mean (standard deviation) headache frequency of our training and testing datasets were 13.4 (10.9) and 14.4 (11.2), respectively. The GPT-2 generative model was the best-performing model with an accuracy of 0.92 (0.91, 0.93, 95% confidence interval [CI]) and R2 score of 0.89 (0.87, 0.90, 95% CI), and all GPT-2-based models outperformed the ClinicalBERT model in terms of exact matching accuracy. Although the ClinicalBERT regression model had the lowest accuracy of 0.27 (0.26, 0.28), it demonstrated a high R2 score of 0.88 (0.85, 0.89), suggesting the ClinicalBERT model can reasonably predict the headache frequency within a range of ≤ ± 3 days, and the R2 score was higher than the GPT-2 QA zero-shot model or GPT-2 QA model few-shot training fine-tuned model. CONCLUSION: We developed a robust information extraction model based on a state-of-the-art large language model, a GPT-2 generative model that can extract headache frequency from EHR free-text clinical notes with high accuracy and R2 score. It overcame several challenges related to different ways clinicians document headache frequency that were not easily achieved by traditional NLP models. We also showed that GPT-2-based frameworks outperformed ClinicalBERT in terms of accuracy in extracting headache frequency from clinical notes. To facilitate research in the field, we released the GPT-2 generative model and inference code with open-source license of community use in GitHub. Additional fine-tuning of the algorithm might be required when applied to different health-care systems for various clinical use cases.

Cigarette smoking decline among US young adults from 2000 to 2019, in relation to state-level cigarette price and tobacco control expenditure.

OBJECTIVE: To investigate the association of state-level cigarette price and tobacco control expenditure with the large 2000-2019 decline in cigarette smoking among US 18-24 year-olds. METHODS: Smoking behaviour was assessed in the 24 most populous US states using the 1992-2019 Tobacco Use Supplements to the Current Population Survey; association with price and expenditure was tested using adjusted logistic regression. States were ranked by inflation-adjusted average price and tobacco control expenditure and grouped into tertiles. State-specific time trends were estimated, with slope changes in 2001/2002 and 2010/2011. RESULTS: Between 2000 and 2010, the odds of smoking among US young adults decreased by a third (adjusted OR, AOR 0.68, 95% CI 0.56 to 0.84). By 2019, these odds were one-quarter of their 2000 level (AOR 0.24, 95% CI 0.19 to 0.31). Among states in the lowest tertile of price/expenditure tobacco control activity, initially higher young adult smoking decreased by 13 percentage points from 2010 to 2018-2019, to a prevalence of 5.6% (95% CI 4.5% to 6.8%), equal to that in the highest tobacco-control tertile of states (6.5%, 95% CI 5.2% to 7.8%). Neither state tobacco control spending (AOR 1.0, 95% CI 0.999 to 1.002) nor cigarette price (AOR 0.96, 95% CI: 0.92 to 1.01) were associated with young adult smoking in statistical models. In 2019, seven states had prevalence over 3 SDs higher than the 24-state mean. CONCLUSION: National programmes may have filled a gap in state-level interventions, helping drive down the social acceptability of cigarette smoking among young adults across all states. Additional interventions are needed to assist high-prevalence states to further reduce smoking.

Imbalance of gut microbiota in gestational diabetes.

AIM: To investigate the differences in gut microbiota composition among nonpregnant women of reproductive age, healthy pregnant women, and gestational diabetes (GD) patients. METHODS: A total of 45 outpatients were enrolled and divided into three groups: nonpregnant women of reproductive age (control group, n = 23), healthy pregnant women (normal group, n = 10), and GD patients (GD group, n = 12). Faecal samples were collected and sequenced using 16S rRNA gene sequencing to analyse the microbial composition. RESULTS: (1) Pregnant patients exhibited an increase in the abundance of Streptococcus (Pnormal = 0.01286, PGD = 0.002965) and Blautia (Pnormal = 0.0003924, PGD = 0.000246) but a decrease in the abundance of Roseburia (Pnormal = 0.0361, PGD = 0.007075), Phascolarctobacterium (Pnormal = 0.0003906, PGD = 0.02499) and Lachnoclostridium (Pnormal = 0.0003906, PGD = 0.03866). (2) Compared with healthy pregnant women, GD patients had an excessive increase in Streptococcus abundance and decrease in Roseburia abundance. The increase in Blautia abundance and the decrease in Phascolarctobacterium and Lachnoclostridium abundance in GD patients were less than those in healthy pregnant women. (3) The abundance of Faecalibacterium prausnitzii decreased significantly in GD patients (PGD = 0.02985) but not in healthy pregnant patients (Pnormal = 0.1643). CONCLUSIONS: Abnormal increases and decreases in the abundances of gut microbiota components, especially Faecalibacterium prausnitzii, were observed in GD patients. TRIAL REGISTRATION: The cross-sectional research was conducted in accordance with the Declaration of Helsinki, and approved by Sir Run Run Shaw Hospital Clinical Trials and Biomedical Ethics Committee. The study has been registered in the Chinese Clinical Trial Registry (ChiCTR1900026164, 24/09/2019, http://www.chictr.org.cn/showproj.aspx?proj=43,455 ).

Comprehensively evaluating the relationships between marital status and other family factors with cardiovascular disease and long-term overall mortality in the elderly: a study of 48 510 Chinese individuals.

BACKGROUND: Marital status is associated with cardiovascular disease (CVD) incidence and overall mortality, yet limited research on this topic in elderly individuals is available. Our aim was to comprehensively assess the impact of marital status and other family factors on CVD incidence and long-term mortality among elderly people. METHODS: Data from the Chinese Longitudinal Healthy Longevity Survey (2002/2005/2008-2018) for participants aged ≥60 years were analysed. A cross-sectional study initially examined the correlation between spouses, offspring, living arrangements, and CVD using logistic regression. Subsequently, a retrospective cohort study investigated the long-term associations of these factors with overall mortality via Kaplan-Meier and Cox regression analyses. RESULTS: The study involved 48 510 subjects (average age: 87 years). The cross-sectional analysis revealed a correlation between living with a spouse and an increased incidence of heart disease (adjusted OR 1.27, 95% CI 1.04-1.55) and cerebrovascular disease/stroke (adjusted OR 1.26, 95% CI 1.11-1.42). According to the retrospective cohort analysis, living with a spouse significantly reduced overall mortality (adjusted HR 0.84, 95% CI 0.80-0.87), irrespective of marital relationship quality. Conversely, living with offspring (adjusted HR 1.12, 95% CI 1.08-1.16), having more children (adjusted Pnonlinearity = 0.427) or cohabitants (adjusted Pnonlinearity < 0.0001) were associated with increased overall mortality. CONCLUSION: In the elderly population, being married and living with a spouse were not significantly associated with a decrease in CVD incidence but were associated with a reduction in long-term overall mortality. Living with offspring, having more children, or having a larger family size did not replicate the protective effect but indicated greater overall mortality.

Development and validation of a risk prediction model for community-acquired pressure injury in a cancer population: A case-control study.

BACKGROUND: Patients with cancer are susceptible to pressure injuries, which accelerate deterioration and death. In patients with post-acute cancer, the risk of pressure injury is ignored in home or community settings. OBJECTIVE: To develop and validate a community-acquired pressure injury risk prediction model for cancer patients. METHODS: All research data were extracted from the hospital's electronic medical record system. The identification of optimal predictors is based on least absolute shrinkage and selection operator regression analysis combined with clinical judgment. The performance of the model was evaluated by drawing a receiver operating characteristic curve and calculating the area under the curve (AUC), calibration analysis and decision curve analysis. The model was used for internal and external validation, and was presented as a nomogram. RESULTS: In total, 6257 participants were recruited for this study. Age, malnutrition, chronic respiratory failure, body mass index, and activities of daily living scores were identified as the final predictors. The AUC of the model in the training and validation set was 0.87 (95 % confidence interval [CI], 0.85-0.89), 0.88 (95 % CI, 0.85-0.91), respectively. The model demonstrated acceptable calibration and clinical benefits. CONCLUSIONS: Comorbidities in patients with cancer are closely related to the etiology of pressure injury, and can be used to predict the risk of pressure injury. IMPLICATIONS FOR PRACTICE: This study provides a tool to predict the risk of pressure injury for cancer patients. This suggests that improving the respiratory function and nutritional status of cancer patients may reduce the risk of community-acquired pressure injury.

[Correlation of sperm HDS with sperm DFI and morphology and its influence on in vitro fertilization in infertile males].

OBJECTIVE: To invest the correlation of sperm high DNA stainability (HDS) with sperm DNA fragmentation index (DFI) and sperm abnormalities and its influence on in vitro fertilization (IVF) in male infertility patients, and assess the clinical value of HDS. METHODS: Using flow cytometry-assisted sperm chromatin structure assay (SCSA), we examined sperm HDS and sperm DFI in 322 male infertility patients undergoing IVF due to female fallopian tube factors only. Based on sperm HDS, we divided the patients into five groups and compared the semen routine parameters, percentage of morphologically abnormal sperm (MAS), sperm DFI, rates of fertilization, cleavage and high-quality embryos, and pregnancy outcomes among different HDS groups. RESULTS: Among the 322 male infertility patients, 119 (36.96%) were found with a sperm HDS of 0 － <5%, 117 (36.34%) of 5% － <10%, 50 (15.53%) of 10% － <15%, 23 (7.14%) of 15% － <20%, and 13 (4.03%) of ≥20%. Sperm concentration, motility and progressive motility were decreased with the increase of sperm HDS, but with no statistically significant difference (P > 0.05), so were the rates of fertilization, high-quality embryos and pregnancy (P > 0.05). Sperm DFI and sperm abnormality were correlated positively with sperm HDS (r = 0.236, r = 0.203). The rate of early abortion was remarkably increased in those with sperm HDS greater than 10%. CONCLUSION: Sperm HDS may be a risk indicator of sperm DFI and sperm abnormality, and can be used as a predictive indicator of early abortion in IVF.

[Advancements in virtual screening techniques for study of enzyme inhibitor compounds].

Enzymes are closely associated with the onset and progression of numerous diseases, making enzymes a primary target in innovative drug development. However, the challenge remains in identifying compounds that exhibit potent inhibitory effects on the target enzymes. With the continuous expansion of the total number of natural products and increasing difficulty in isolating and enriching new compounds, traditional high-throughput screening methods are finding it increasingly challenging to meet the demands of new drug development. Virtual screening, characterized by its high efficiency and low cost, has gradually become an indispensable technology in drug development. It represents a prominent example of the integration of artificial intelligence with biopharmaceuticals and is an inevitable trend in the rapid development of innovative drug screening in the future. Therefore, this article primarily focused on systematically reviewing the recent applications of virtual screening technology in the development of enzyme inhibitors and explored the prospects and advantages of using this technology in developing new drugs, aiming to provide essential theoretical insights and references for the application of related technologies in the field of new drug development.

Tanshinone IIA improves Alzheimer's disease via RNA nuclear-enriched abundant transcript 1/microRNA-291a-3p/member RAS oncogene family Rab22a axis.

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative condition characterized by oxidative stress and neuroinflammation. Tanshinone IIA (Tan-IIA), a bioactive compound isolated from Salvia miltiorrhiza plants, has shown potential neuroprotective effects; however, the mechanisms underlying such a function remain unclear. AIM: To investigate potential Tan-IIA neuroprotective effects in AD and to elucidate their underlying mechanisms. METHODS: Hematoxylin and eosin staining was utilized to analyze structural brain tissue morphology. To assess changes in oxidative stress and neuroinflammation, we performed enzyme-linked immunosorbent assay and western blotting. Additionally, the effect of Tan-IIA on AD cell models was evaluated in vitro using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Genetic changes related to the long non-coding RNA (lncRNA) nuclear-enriched abundant transcript 1 (NEAT1)/microRNA (miRNA, miR)-291a-3p/member RAS oncogene family Rab22a axis were assessed through reverse transcription quantitative polymerase chain reaction. RESULTS: In vivo, Tan-IIA treatment improved neuronal morphology and attenuated oxidative stress and neuroinflammation in the brain tissue of AD mice. In vitro experiments showed that Tan-IIA dose-dependently ameliorated the amyloid-beta 1-42-induced reduction of neural stem cell viability, apoptosis, oxidative stress, and neuroinflammation. In this process, the lncRNA NEAT1 - a potential therapeutic target - is highly expressed in AD mice and downregulated via Tan-IIA treatment. Mechanistically, NEAT1 promotes the transcription and translation of Rab22a via miR-291a-3p, which activates nuclear factor kappa-B (NF-κB) signaling, leading to activation of the pro-apoptotic B-cell lymphoma 2-associated X protein and inhibition of the anti-apoptotic B-cell lymphoma 2 protein, which exacerbates AD. Tan-IIA intervention effectively blocked this process by inhibiting the NEAT1/miR-291a-3p/Rab22a axis and NF-κB signaling. CONCLUSION: This study demonstrates that Tan-IIA exerts neuroprotective effects in AD by modulating the NEAT1/miR-291a-3p/Rab22a/NF-κB signaling pathway, serving as a foundation for the development of innovative approaches for AD therapy.

Rhythm gene PER1 mediates ferroptosis and lipid metabolism through SREBF2/ALOX15 axis in polycystic ovary syndrome.

OBJECTIVE: This work aimed to investigate the role of rhythm gene PER1 in mediating granulosa cell ferroptosis and lipid metabolism of polycystic ovary syndrome (PCOS). METHODS: We injected dehydroepiandrosterone and Ferrostatin-1 (Fer-1) into mice to explore the mechanism of ferroptosis in PCOS. The effect of PER1 on ferroptosis-like changes in granulosa cells was explored by overexpression of PER1 plasmid transfection and Fer-1 treatment. RESULTS: We found that Fer-1 ameliorated the characteristic polycystic ovary morphology, suppressed ferroptosis in the PCOS mice. PER1 and ALOX15 were highly expressed in PCOS, whereas SREBF2 was lowly expressed. Overexpression of PER1 decreased granulosa cell viability and inhibited proliferation. Meanwhile, overexpression of PER1 increased lipid reactive oxygen species, 4-Hydroxynonenal (4-HNE), Malondialdehyde (MDA), total Fe, and Fe2+ levels in granulosa cells and decreased Glutathione (GSH) content. Fer-1, SREBF2 overexpression, or ALOX15 silencing treatment reversed the effects of PER1 overexpression on granulosa cells. PER1 binds to the SREBF2 promoter and represses SREBF2 transcription. SREBF2 binds to the ALOX15 promoter and represses ALOX15 transcription. Correlation analysis of clinical trials showed that PER1 was positively correlated with total cholesterol, low-density lipoprotein cholesterol, luteinizing hormone, testosterone, 4-HNE, MDA, total Fe, Fe2+, and ALOX15. In contrast, PER1 was negatively correlated with SREBF2, high-density lipoprotein cholesterol, follicle-stimulating hormone, progesterone, and GSH. CONCLUSION: This study demonstrates that the rhythm gene PER1 promotes ferroptosis and dysfunctional lipid metabolism in granulosa cells in PCOS by inhibiting SREBF2/ALOX15 signaling.

Estimated bone mineral density and white matter hyperintensities: A bidirectional Mendelian randomization study.

PURPOSE: Greater white matter hyperintensities (WMH) in older adults have been associated with reduced bone mineral density (BMD) and increased fractures and falls. However, it is unclear whether there is a causal relationship between BMD reduction and WMH. In this study, Mendelian randomization (MR) was used to find the causality between WMH and estimated BMD (eBMD). METHODS: We performed a two-sample bidirectional MR analysis using statistical data obtained from publicly available genome-wide association studies (GWAS). The main method of MR analysis is the inverse-variance weighted (IVW) method. To identify and account for the impact of horizontal pleiotropy, we also employed MR-Egger regression, MR pleiotropy residual sum, and outlier (MR-PRESSO). RESULTS: MR analysis found a causal relationship between eBMD and WMH (IVW OR = 0.938, 95 % CI: 0.889-0.990, p = 0.020). Our causal estimates are unlikely to be distorted by horizontal pleiotropy according to heterogeneity test (both p > 0.05) and MR-Egger regression (p > 0.05). However, in the reverse MR analysis, there was no evidence that WMH was causally correlated with eBMD (IVW OR = 0.979, 95 % CI: 0.954-1.005, p = 0.109). CONCLUSION: Our results suggest that low eBMD increased the risk of WMH; conversely, no evidence that WMH causally affects eBMD was found.

ATR/Chk1 interacting lncRNA modulates DNA damage response to induce breast cancer chemoresistance.

The ATR-Chk1 pathway is essential in cellular responses to DNA damage and replication stress, whereas the role of long noncoding RNAs (lncRNAs) in regulating this pathway remains largely unknown. In this study, we identify an ATR and Chk1 interacting lncRNA (ACIL, also known as LRRC75A-AS1 or SNHG29), which promotes the phosphorylation of Chk1 by ATR upon DNA damages. High ACIL levels are associated with chemoresistance to DNA damaging agents and poor outcome of breast cancer patients. ACIL knockdown sensitizes breast cancer cells to DNA damaging drugs in vitro and in vivo. ACIL protects cancer cells against DNA damages by inducing cell cycle arrest, stabilizing replication forks and inhibiting unscheduled origin firing, thereby guarding against replication catastrophe and contributing to DNA damage repair. These findings demonstrate a lncRNA-dependent mechanism of activating the ATR-Chk1 pathway and highlight the potential of utilizing ACIL as a predictive biomarker for chemotherapy sensitivity, as well as targeting ACIL to reverse chemoresistance in breast cancer.

Expression of IL-4 and IL-12 in the aqueous humor of patients with chronic primary angle-closure glaucoma.

Introduction: Angle-closure glaucoma is a common type of glaucoma in Asian populations. However, the role of inflammatory cytokines in angle-closure glaucoma is yet to be elucidated. Therefore, this study aimed to examine the expression of interleukin-4 (IL-4) and IL-12 in the aqueous humor of patients with chronic primary angle-closure glaucoma (CPACG) and elucidate the correlations between IL-4 and IL-12 concentrations in the aqueous humor, the degree of visual field defects, and retinal nerve fiber layer (RNFL) thickness in patients with CPACG. Methods: Aqueous humor samples were obtained from 31 patients diagnosed with CPACG at the Shaoxing People's Hospital between April 2022 and March 2023 and from 30 individuals with cataract (control). Based on the degree of the mean defect (MD), patients were divided into three groups: group A (MD ≤ -6dB, n= 10), group B (-6dB< MD< -12dB, n= 9), and group C (MD ≥ - 12dB, n= 12). RNFL thickness was measured using an optical coherence tomograph, and the concentrations of IL-4 and IL-12 in the aqueous humor were measured using Luminex technology. Results: Aqueous humor concentration of IL-4 was significantly higher (p = 0.036) in the CPACG group than in the cataract group. However, there was no significant difference (p > 0.05) in IL- 12 concentration between the two groups. Additionally, there were no significant differences (p > 0.05) in IL-4 and IL-12 levels among patients with varying degrees of visual field defects (groups A, B, and C). Spearman's correlation analysis showed that IL-4 and IL-12 concentrations were not correlated (p > 0.05) with RNFL thickness around the optic disc and the degree of visual field defects. Discussion: Conclusively, IL-4 may play an important role in the pathogenesis of CPACG. Given that IL-4 and IL-12 concentrations in the aqueous humor were not significantly correlated with RNFL thickness and the degree of visual field defects, the increase in IL-4 and IL-12 expression may not induce apoptosis and loss of retinal ganglion cells or affect RNFL thickness as well as the degree of visual field defects.

Psychometrics of the modified Family-Centered Care Assessment short version for childhood obesity.

Background: Incorporating principles of family-centered care into pediatric weight management interventions can improve the effectiveness and quality of treatment and reduce attrition rates. To assess the family-centeredness of interventions, reliable, valid, and easy-to-administer scales are needed. The purpose of the study was to develop a shortened version of the modifed Family Centered Care Assessment (mFCCA) and assess its psychometric properties. Methods: The mFCCA, a scale to assess the family-centeredness of interventions for childhood obesity, was administered to families following the Connect for Health randomized control trial evaluating the effectiveness of a primary care-based pediatric weight management intervention. We iteratively removed items from the mFCCA and used Rasch modeling to examine the reliability and validity of the shortened scale. Results: We included data from 318 parents and the exploratory factor analysis showed the presence of a single factor. The results of the Rasch modeling demonstrated acceptable internal consistency of the scale (0.7) and strong validity as evidenced by the overall model fit and range of item difficulty. Following the psychometric analyses, we reduced the number of items from 24 to 8 items. Conclusions: The mFCCA short version demonstrates good psychometrics and can be used to evaluate the family-centeredness of childhood obesity interventions with reduced participant burden, thereby improving outcomes for children with obesity. Trial registration: Clinicaltrials.gov NCT02124460 registered on April 24, 2014.

The Association of Intraindividual Difference Between Cystatin- and Creatinine-Based Estimated GFR and Contrast-Associated Acute Kidney Injury.

Purpose: The estimated glomerular filtration rate (eGFR) based on creatinine is crucial for the risk assessment of contrast-associated acute kidney injury (CA-AKI). In recent, the difference between cystatin C-based eGFR (eGFRcys) and creatinine-based eGFR (eGFRcr) has been widely documented. We aimed to explore whether intraindividual differences between eGFRcys and eGFRcr had potential value for CA-AKI risk assessment in patients undergoing elective percutaneous coronary intervention (PCI). Patients and Methods: From January 2012 to December 2018, we retrospectively observed 5049 patients receiving elective PCI. To determine eGFR, serum creatinine and cystatin C levels were measured. CA-AKI was defined as serum creatinine being increased ≥ 50% or 0.3 mg/dL within 48 h after contrast agents exposure. Chronic kidney disease (CKD) was defined as the eGFR < 60 mL/min/1.73 m2. Results: Approximately half of the participants (2479, 49.1%) had a baseline eGFRdiff (eGFRcys-eGFRcr) between -15 and 15 mL/min/1.73 m2. Restricted cubic splines analysis revealed a nonlinear relationship between eGFRdiff and CA-AKI. Multivariable logistic regression analysis indicated that compared with the reference group (-15 to 15 mL/min/1.73 m2), the negative-eGFRdiff group (less than -15 mL/min/1.73 m2) had a higher risk of CA-AKI (OR, 3.44; 95% CI, 2.57-4.64). Furthermore, patients were divided into four groups based on CKD identified by eGFRcys or eGFRcr. Multivariable logistic analysis revealed that patients with either CKDcys (OR, 2.94; 95% CI, 2.19-3.95, P < 0.001) or CKDcr (OR, 2.44; 95% CI, 1.19-4.63, P < 0.001) had an elevated risk of CA-AKI compared to those without CKDcys and CKDcr. Conclusion: There are frequent intraindividual differences between eGFRcys and eGFRcr, and these differences can be used to forecast the risk of CA-AKI.

Gastric-filling ultrasonography to evaluate gastric motility in patients with Parkinson's disease.

Background: Delayed gastric emptying is a common non-motor symptom of Parkinson's disease (PD). However, there is currently no objective evaluation and diagnostic method for this condition. Objectives: The purpose of this study was to evaluate the feasibility of gastric-filling ultrasonography for gastric motility in patients with PD and the relationship between gastric dynamics and gastrointestinal symptoms and motor symptoms of PD. Design setting and patients: We performed a case-control study with 38 patients with PD and 34 healthy controls. Methods: All patients underwent a 120-min ultrasonography examination using a 500-ml semi-liquid test meal. We determined the antral contraction amplitude (ACA), the antrum contraction frequency (ACF), the motility index (MI), and the gastric antral cross-sectional area (CSA). We acquired the CSA at six time points: fasting for 12 h (T0), immediately after drinking the semi-liquid test meal (T1); and at 30 (T30), 60 (T60), 90 (T90), and 120 (T120) min. We calculated the gastric emptying rate (GER) at different time points by using the CSA. We compared the GER between the groups and evaluated the correlation between the GER and gastrointestinal symptoms and motor symptoms of PD. Results: The MI and ACF were significantly lower in the PD group compared with the control group (P < 0.05). The GER at T30 and the ACA showed no significant difference between the groups (P > 0.05). At different time points, the GER was significantly different between the PD and control groups (P < 0.001). There was no significant association between the GER and gastrointestinal symptoms; none of them were risk factors for impaired gastric emptying (odds ratio > 1). The GER was negatively correlated with the severity of PD motor symptoms (P < 0.05). Conclusion: Patients with PD had significantly delayed gastric emptying, which was negatively correlated with the severity of PD motor symptoms. Measuring gastric emptying by gastric-filling ultrasound had good diagnostic value in clinical screening for delayed gastric motility in patients with PD. Clinical Trial Registration: https://www.chictr.org.cn/showproj.html?proj=126304.

High-Sensitivity Optical Sensors Empowered by Quasi-Bound States in the Continuum in a Hybrid Metal-Dielectric Metasurface.

Enhancing light-matter interaction is a key requisite in the realm of optical sensors. Bound states in the continuum (BICs), possessing high quality factors (Q factors), have shown great advantages in sensing applications. Recent theories elucidate the ability of BICs with hybrid metal-dielectric architectures to achieve high Q factors and high sensitivities. However, the experimental validation of the sensing performance in such hybrid systems remains equivocal. In this study, we propose two symmetry-protected quasi-BIC modes in a metal-dielectric metasurface. Our results demonstrate that, under the normal incidence of light, the quasi-BIC mode dominated by dielectric can achieve a high Q factor of 412 and a sensing performance with a high bulk sensitivity of 492.7 nm/RIU (refractive index unit) and a figure of merit (FOM) of 266.3 RIU-1, while the quasi-BIC mode dominated by metal exhibits a stronger surface affinity in the biotin-streptavidin bioassay. These findings offer a promising approach for implementing metasurface-based sensors, representing a paradigm for high-sensitivity biosensing platforms.