Effect of ethanol on the elasticities of double-stranded RNA and DNA revealed by magnetic tweezers and simulations.

The elasticities of double-stranded (ds) DNA and RNA, which are critical to their biological functions and applications in materials science, can be significantly modulated by solution conditions such as ions and temperature. However, there is still a lack of a comprehensive understanding of the role of solvents in the elasticities of dsRNA and dsDNA in a comparative way. In this work, we explored the effect of ethanol solvent on the elasticities of dsRNA and dsDNA by magnetic tweezers and all-atom molecular dynamics simulations. We found that the bending persistence lengths and contour lengths of dsRNA and dsDNA decrease monotonically with the increase in ethanol concentration. Furthermore, the addition of ethanol weakens the positive twist-stretch coupling of dsRNA, while promotes the negative twist-stretch coupling of dsDNA. Counter-intuitively, the lower dielectric environment of ethanol causes a significant re-distribution of counterions and enhanced ion neutralization, which overwhelms the enhanced repulsion along dsRNA/dsDNA, ultimately leading to the softening in bending for dsRNA and dsDNA. Moreover, for dsRNA, ethanol causes slight ion-clamping across the major groove, which weakens the major groove-mediated twist-stretch coupling, while for dsDNA, ethanol promotes the stretch-radius correlation due to enhanced ion binding and consequently enhances the helical radius-mediated twist-stretch coupling.

The art of fixing a ticking time bomb: Combined phacoemulsification and amniotic membrane transplantation.

Bleb leakage is a notorious complication of glaucoma filtration surgery which increases the risk of sight-threatening conditions. A 25-year-old female with severe bilateral juvenile open-angle glaucoma was treated for blebitis and exogenous endophthalmitis secondary to chronic bleb leak after undergoing XEN implantation, followed by multiple rounds of bleb needling, and augmented trabeculectomy. In the right eye, visual acuity was hand movement with cataract, intraocular pressure was 6 mmHg and the bleb was large, highly elevated from 10 to 1 o'clock, avascular, thin wall, and cystic with leaking points. Combined surgery of low-setting phacoemulsification and amniotic membrane transplantation without excising and manipulating the bleb was performed in the same setting. At postoperative 1 month, 6 months, and 1 year, her right vision had improved to 6/24, and the intraocular pressure was 12-14 mmHg, and the bleb leakage had resolved. This successful treatment was accomplished by maintaining the bleb's viability, preventing additional injury, and promoting wound healing.

Analysis of cancer-specific survival in patients with metastatic colorectal cancer: A evidence-based medicine study.

BACKGROUND: Metastatic colorectal cancer (mCRC) is a common malignancy whose treatment has been a clinical challenge. Cancer-specific survival (CSS) plays a crucial role in assessing patient prognosis and treatment outcomes. However, there is still limited research on the factors affecting CSS in mCRC patients and their correlation. AIM: To predict CSS, we developed a new nomogram model and risk grading system to classify risk levels in patients with mCRC. METHODS: Data were extracted from the United States Surveillance, Epidemiology, and End Results database from 2018 to 2023. All eligible patients were randomly divided into a training cohort and a validation cohort. The Cox proportional hazards model was used to investigate the independent risk factors for CSS. A new nomogram model was developed to predict CSS and was evaluated through internal and external validation. RESULTS: A multivariate Cox proportional risk model was used to identify independent risk factors for CSS. Then, new CSS columns were developed based on these factors. The consistency index (C-index) of the histogram was 0.718 (95%CI: 0.712-0.725), and that of the validation cohort was 0.722 (95%CI: 0.711-0.732), indicating good discrimination ability and better performance than tumor-node-metastasis staging (C-index: 0.712-0.732). For the training set, 0.533, 95%CI: 0.525-0.540; for the verification set, 0.524, 95%CI: 0.513-0.535. The calibration map and clinical decision curve showed good agreement and good potential clinical validity. The risk grading system divided all patients into three groups, and the Kaplan-Meier curve showed good stratification and differentiation of CSS between different groups. The median CSS times in the low-risk, medium-risk, and high-risk groups were 36 months (95%CI: 34.987-37.013), 18 months (95%CI: 17.273-18.727), and 5 months (95%CI: 4.503-5.497), respectively. CONCLUSION: Our study developed a new nomogram model to predict CSS in patients with synchronous mCRC. In addition, the risk-grading system helps to accurately assess patient prognosis and guide treatment.

A new species of Cincticostella Allen, 1971 (Ephemeroptera, Ephemerellidae) from Yunnan, China and establishment of a new species complex.

Cincticostellajianchuan sp. nov. from Dali Bai Autonomous Prefecture, Yunnan Province, China, is described based on chorionic structure, nymph, and winged stages. The new species is closely related to C.fusca (Kang & Yang, 1995), but it can be distinguished in the male imago stage by its mesonotum and penes morphology, coloration, and the forking point of the stem of MA+Rs on the forewing; in the nymph stage, it can be distinguished by the length of the posterolateral projections of abdominal segment IX and the setation of the abdominal terga. Compared to other congeners, nymphs and male imagoes of the new species and C.fusca share several morphological characteristics, such as a larger body, mesothorax with medially notched anterolateral projections, forefemur without a subapical band of transverse spines of the nymphs, the area between C, Sc and R1 of the forewings distinctly pigmented, and an apical sclerite on the ventral face of the penes of the male imagoes, supporting the proposition of a new species complex, the jianchuan complex. The systematics of Cincticostella and related genera are discussed briefly.

A High Visceral-to-Skeletal Muscle Area Ratio on Cross-Sectional Imaging Is Associated With Failure of Standard Ustekinumab Doses: A Multicenter Study.

INTRODUCTION: Anti-interleukin 12/23 agents have shown greater durability in response compared with anti-tumor necrosis factor α agents. Data on the association between body composition (BC) or body mass index (BMI) and ustekinumab's therapeutic response is limited. We aimed to evaluate the impact of BC on time to failing standard doses of ustekinumab in patients with Crohn's disease (CD). METHOD: Patients with CD aged 16 years and older from 2 tertiary centers were studied retrospectively. Included patients had abdominal imaging within 6 months of ustekinumab induction and were followed until April 30, 2022. An experienced abdominal radiologist blinded to the clinical information measured the area of visceral fat area and skeletal muscle area at the mid L3 vertebral level, with values corrected for height 2 to derive respective indices (visceral fat index [VFI], skeletal muscle index [SMI]) and the VFI:SMI ratio. RESULTS: Ninety-nine patients met inclusion criteria. The mean age at ustekinumab induction was 46.6 (±1.6) years. The median BMI (interquartile range) was 26.5 (22.6-30.8). Twenty-four patients (24.2%) did not respond or lost response to standard doses of ustekinumab over the follow-up duration. A younger age (hazard ratio 0.96, 95% confidence interval 0.94-0.99, P = 0.01) and a VFI:SMI ratio >1.6 (hazard ratio 4.65, 95% confidence interval 1.73-12.45, P = 0.002) were both associated with a shorter time to failing ustekinumab at standard doses on multivariate analysis. BMI, notably, had no association with the primary outcome. DISCUSSION: A high VFI:SMI ratio is associated with an increased risk of failing standard doses of ustekinumab. BC measurements derived from cross-sectional imaging at the start of ustekinumab therapy is a useful indicator for therapeutic durability.

Identification and validation of potential diagnostic signature and immune cell infiltration for HIRI based on cuproptosis-related genes through bioinformatics analysis and machine learning.

Background and aims: Cuproptosis has emerged as a significant contributor in the progression of various diseases. This study aimed to assess the potential impact of cuproptosis-related genes (CRGs) on the development of hepatic ischemia and reperfusion injury (HIRI). Methods: The datasets related to HIRI were sourced from the Gene Expression Omnibus database. The comparative analysis of differential gene expression involving CRGs was performed between HIRI and normal liver samples. Correlation analysis, function enrichment analyses, and protein-protein interactions were employed to understand the interactions and roles of these genes. Machine learning techniques were used to identify hub genes. Additionally, differences in immune cell infiltration between HIRI patients and controls were analyzed. Quantitative real-time PCR and western blotting were used to verify the expression of the hub genes. Results: Seventy-five HIRI and 80 control samples from three databases were included in the bioinformatics analysis. Three hub CRGs (NLRP3, ATP7B and NFE2L2) were identified using three machine learning models. Diagnostic accuracy was assessed using a receiver operating characteristic (ROC) curve for the hub genes, which yielded an area under the ROC curve (AUC) of 0.832. Remarkably, in the validation datasets GSE15480 and GSE228782, the three hub genes had AUC reached 0.904. Additional analyses, including nomograms, decision curves, and calibration curves, supported their predictive power for diagnosis. Enrichment analyses indicated the involvement of these genes in multiple pathways associated with HIRI progression. Comparative assessments using CIBERSORT and gene set enrichment analysis suggested elevated expression of these hub genes in activated dendritic cells, neutrophils, activated CD4 memory T cells, and activated mast cells in HIRI samples versus controls. A ceRNA network underscored a complex regulatory interplay among genes. The genes mRNA and protein levels were also verified in HIRI-affected mouse liver tissues. Conclusion: Our findings have provided a comprehensive understanding of the association between cuproptosis and HIRI, establishing a promising diagnostic pattern and identifying latent therapeutic targets for HIRI treatment. Additionally, our study offers novel insights to delve deeper into the underlying mechanisms of HIRI.

Identification of a pathogenic SMCHD1 variant in a Chinese patient with bosma arhinia microphthalmia syndrome: a case report.

BACKGROUND: Bosma arhinia microphthalmia syndrome (BAMS; MIM603457) is a rare genetic disorder, predominantly autosomal dominant. It is a multi-system developmental disorder characterized by severe hypoplasia of the nose and eyes, and reproductive system defects. BAMS is extremely rare in the world and no cases have been reported in Chinese population so far. Pathogenic variants in the SMCHD1 gene (MIM614982) cause BAMS, while the underlying molecular mechanisms requires further investigation. CASE PRESENTATION: In this study, a Chinese girl who has suffered from congenital absence of nose and microphthalmia was enrolled and subsequently submitted to a comprehensive clinical and genetic evaluation. Whole-exome sequencing (WES) was employed to identify the genetic entity of thisgirl. A heterozygous pathogenic variant, NM_015295, c.1025G > C; p. (Trp342Ser) of SMCHD1 was identified. By performing very detailed physical and genetic examinations, the patient was diagnosed as BAMS. CONCLUSION: This report is the first description of a variant in SMCHD1 in a Chinese patient affected with BAMS.Our study not only furnished valuable genetic data for counseling of BAMS, but also confirmed the diagnosis of BAMS, which may help the management and prognosis for this patient.

Identification of potent pan-ephrin receptor kinase inhibitors using DNA-encoded chemistry technology.

EPH receptors (EPHs), the largest family of tyrosine kinases, phosphorylate downstream substrates upon binding of ephrin cell surface-associated ligands. In a large cohort of endometriotic lesions from individuals with endometriosis, we found that EPHA2 and EPHA4 expressions are increased in endometriotic lesions relative to normal eutopic endometrium. Because signaling through EPHs is associated with increased cell migration and invasion, we hypothesized that chemical inhibition of EPHA2/4 could have therapeutic value. We screened DNA-encoded chemical libraries (DECL) to rapidly identify EPHA2/4 kinase inhibitors. Hit compound, CDD-2693, exhibited picomolar/nanomolar kinase activity against EPHA2 (Ki: 4.0 nM) and EPHA4 (Ki: 0.81 nM). Kinome profiling revealed that CDD-2693 bound to most EPH family and SRC family kinases. Using NanoBRET target engagement assays, CDD-2693 had nanomolar activity versus EPHA2 (IC50: 461 nM) and EPHA4 (IC50: 40 nM) but was a micromolar inhibitor of SRC, YES, and FGR. Chemical optimization produced CDD-3167, having picomolar biochemical activity toward EPHA2 (Ki: 0.13 nM) and EPHA4 (Ki: 0.38 nM) with excellent cell-based potency EPHA2 (IC50: 8.0 nM) and EPHA4 (IC50: 2.3 nM). Moreover, CDD-3167 maintained superior off-target cellular selectivity. In 12Z endometriotic epithelial cells, CDD-2693 and CDD-3167 significantly decreased EFNA5 (ligand) induced phosphorylation of EPHA2/4, decreased 12Z cell viability, and decreased IL-1ß-mediated expression of prostaglandin synthase 2 (PTGS2). CDD-2693 and CDD-3167 decreased expansion of primary endometrial epithelial organoids from patients with endometriosis and decreased Ewing's sarcoma viability. Thus, using DECL, we identified potent pan-EPH inhibitors that show specificity and activity in cellular models of endometriosis and cancer.

Visual Pathway Recovery Post Pituitary Adenoma Surgery: Insights from Retinal Structure, Vascular Density, and Neural Conduction Analysis.

INTRODUCTION: This study investigates how surgery for pituitary adenoma (PA) affects the visual pathway, examining changes in the retina, blood vessel density, and nerve function. Since PAs often impair vision as a result of their location near visual structures, this research is key to understanding and improving vision recovery after surgery. METHODS: Our study is based on a retrospective analysis of the historical data of 28 patients diagnosed with pituitary adenomas. We conducted assessments by reviewing preoperative and postoperative imaging records. These included optical coherence tomography (OCT) for retinal structure analysis, diffusion tensor imaging (DTI) for neural transmission evaluation, and optical coherence tomography angiography for assessing blood vessel density. These tools allowed for a detailed understanding of the structural and functional changes within the visual pathway following PA surgery. RESULTS: OCT findings show postoperative changes in the eye: thinning in average and nasal circumpapillary retinal nerve fiber layer, thickening in macular central 1 mm inner plexus layer, ganglion cell complex, and nasal retinal nerve fiber layer. DTI reveals increased fractional anisotropy (FA) in the left optic chiasm and posterior optic nerve, decreased mid-segment optic nerve FA, and increased apparent diffusion coefficient (ADC) in the right optic chiasm and nerve segments. Early postoperative reduction in radial peripapillary capillaries plexus density is noted. Preoperative ganglion cell layer (GCL) thickness correlates with postoperative visual radiation FA and ADC values, especially in the inferior quadrant. A negative correlation exists between preoperative GCL thickness and postoperative visual field mean defect values, particularly on the temporal side and superior inner ring. All changes are statistically significant (P < 0.05). CONCLUSIONS: The study finds that surgery for PA has varied effects on vision. Early post surgery, there are changes in the retina and nerve signals. Macular GCL thickness before surgery might predict early visual recovery, influencing future research and treatment for vision issues related to PA.

Flexible, biodegradable ultrasonic wireless electrotherapy device based on highly self-aligned piezoelectric biofilms.

Biodegradable piezoelectric devices hold great promise in on-demand transient bioelectronics. Existing piezoelectric biomaterials, however, remain obstacles to the development of such devices due to difficulties in large-scale crystal orientation alignment and weak piezoelectricity. Here, we present a strategy for the synthesis of optimally orientated, self-aligned piezoelectric γ-glycine/polyvinyl alcohol (γ-glycine/PVA) films via an ultrasound-assisted process, guided by density functional theory. The first-principles calculations reveal that the negative piezoelectric effect of γ-glycine originates from the stretching and compression of glycine molecules induced by hydrogen bonding interactions. The synthetic γ-glycine/PVA films exhibit a piezoelectricity of 10.4 picocoulombs per newton and an ultrahigh piezoelectric voltage coefficient of 324 × 10-3 volt meters per newton. The biofilms are further developed into flexible, bioresorbable, wireless piezo-ultrasound electrotherapy devices, which are demonstrated to shorten wound healing by ~40% and self-degrade in preclinical wound models. These encouraging results offer reliable approaches for engineering piezoelectric biofilms and developing transient bioelectronics.

Reversible male contraception by targeted inhibition of serine/threonine kinase 33.

Men or mice with homozygous serine/threonine kinase 33 (STK33) mutations are sterile owing to defective sperm morphology and motility. To chemically evaluate STK33 for male contraception with STK33-specific inhibitors, we screened our multibillion-compound collection of DNA-encoded chemical libraries, uncovered potent STK33-specific inhibitors, determined the STK33 kinase domain structure bound with a truncated hit CDD-2211, and generated an optimized hit CDD-2807 that demonstrates nanomolar cellular potency (half-maximal inhibitory concentration = 9.2 nanomolar) and favorable metabolic stability. In mice, CDD-2807 exhibited no toxicity, efficiently crossed the blood-testis barrier, did not accumulate in brain, and induced a reversible contraceptive effect that phenocopied genetic STK33 perturbations without altering testis size. Thus, STK33 is a chemically validated, nonhormonal contraceptive target, and CDD-2807 is an effective tool compound.

Association Between Dietary Factors and Chronic Sinusitis Among Korean Individuals: Insights From a Large Population-Based Study in Asia.

Objective: Population-based studies on chronic sinusitis have predominantly focused on Europe and the Americas, but research on chronic sinusitis within large Asian populations remains scarce. This study aims to explore the link between dietary factors and chronic sinusitis among ethnic Koreans in Asia. Design: A cross-sectional study. Setting: Data were collected from the Korean National Health and Nutrition Examination Survey (KNHANES) in 2012. Participants: Participants in the study were included based on a doctor's diagnosis of chronic sinusitis, as determined through the ear, nose, and throat examination questionnaires. Results: Adolescents [adjusted P value (aP) < .001, adjusted odds ratio (aOR) = 1.881, 95% confidence interval (CI) = 1.380-2.564] and individuals with college and higher education (aP = .042, aOR = 1.298, 95% CI = 1.009-1.669) were more likely to develop chronic rhinosinusitis. In addition, levels of dietary fat [P = .001, interquartile range (IQR) = 34.085] and energy intake (P = .004, IQR = 981.106) were associated with an increased risk of chronic sinusitis. Moreover, high dietary inflammatory index (aP < .001, aOR = 0.547, 95% CI = 0.415-0.721), and high intake of fried pork chops (aP = .028, aOR = 1.335, 95% CI = 1.033-1.777), bread (aP = .024, aOR = 1.364, 95% CI = 1.042-1.786), and rice (aP = .021, aOR = 1.382, 95% CI = 1.051-1.818) were risk factors for chronic sinusitis, while cucumber consumption (aP < .001, aOR = 0.547, 95% CI = 0.415-0.721) was a protective factor for chronic sinusitis. Conclusion: This study revealed a significant correlation between diet and development of chronic sinusitis. These findings suggest that promoting an anti-inflammatory dietary pattern and providing guidance on healthy eating habits could help reduce the incidence of chronic sinusitis and enhance its management.

Lymph node metastasis prediction and biological pathway associations underlying DCE-MRI deep learning radiomics in invasive breast cancer.

BACKGROUND: The relationship between the biological pathways related to deep learning radiomics (DLR) and lymph node metastasis (LNM) of breast cancer is still poorly understood. This study explored the value of DLR based on dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in LNM of invasive breast cancer. It also analyzed the biological significance of DLR phenotype based on genomics. METHODS: Two cohorts from the Cancer Imaging Archive project were used, one as the training cohort (TCGA-Breast, n = 88) and one as the validation cohort (Breast-MRI-NACT Pilot, n = 57). Radiomics and deep learning features were extracted from preoperative DCE-MRI. After dual selection by principal components analysis (PCA) and relief methods, radiomics and deep learning models for predicting LNM were constructed by the random forest (RF) method. A post-fusion strategy was used to construct the DLR nomograms (DLRNs) for predicting LNM. The performance of the models was evaluated using the receiver operating characteristic (ROC) curve and Delong test. In the training cohort, transcriptome data were downloaded from the UCSC Xena online database, and biological pathways related to the DLR phenotypes were identified. Finally, hub genes were identified to obtain DLR gene expression (RadDeepGene) scores. RESULTS: DLRNs were based on area under curve (AUC) evaluation (training cohort, AUC = 0.98; validation cohort, AUC = 0.87), which were higher than single radiomics models or GoogLeNet models. The Delong test (radiomics model, P = 0.04; GoogLeNet model, P = 0.01) also validated the above results in the training cohorts, but they were not statistically significant in the validation cohort. The GoogLeNet phenotypes were related to multiple classical tumor signaling pathways, characterizing the biological significance of immune response, signal transduction, and cell death. In all, 20 genes related to GoogLeNet phenotypes were identified, and the RadDeepGene score represented a high risk of LNM (odd ratio = 164.00, P < 0.001). CONCLUSIONS: DLRNs combining radiomics and deep learning features of DCE-MRI images improved the preoperative prediction of LNM in breast cancer, and the potential biological characteristics of DLRN were identified through genomics.

Physiology education in China: the current situation and changes over the past 3 decades.

OBJECTIVE: As an experimental biological science, physiology has been taught as an integral component of medical curricula for a long time in China. The teaching effectiveness of physiology courses will directly affect students' learning of other medical disciplines. The purpose of this study is to investigate the current situation and changes in physiology teaching over 30 years in Chinese medical schools. METHODS: National survey was conducted online on the platform SoJump via WeChat and the web. The head of the physiology department in medical school was asked to indicate the information of physiology education from three periods: 1991-2000, 2001-2010, and 2011-2020. The responses of 80 leaders of the Department of Physiology from mainland Chinese medical schools were included in the study for analysis. RESULTS: The survey showed that the class hours, both of theory and practice, had been decreased. During the past 20 years, the total number of physiology teachers, the number of physiology teachers who had been educated in medical schools, and the number of technicians had been reduced, whereas teachers with doctor's degrees had been increased. In addition to traditional didactic teaching, new teaching approaches, including problem-based learning/case-based learning/team-based learning, integrated curriculum and formative evaluation systems, had been employed, mostly for more than 5 years, in some medical schools. CONCLUSION: The present study has provided historical data regarding the current status of physiology education in China and that in the past thirty years by showing that physiology education in China has developed quickly,even it faces many challenges.

Ultra-high piezoelectric properties and ultra-high Curie temperature of Li/Ce-doped La2Ti2O7 ceramics.

The demand for ultra-high-temperature piezoelectric sensors in industrial applications has witnessed a rapid upsurge. In this study, the piezoelectric properties of La2Ti2O7 (LTO) piezoelectric ceramics with a perovskite-like layered structure were enhanced by doping with Li/Ce ions. It was found that a remarkable 300% enhancement in the piezoelectric constant (d33) value was achieved in Li/Ce-doped LTO ceramics compared to their pristine counterparts, reaching 6.4 pC N-1 at room temperature with an ultra-high Curie temperature of 1408 °C. After annealing at 500 °C, the d33 value of the samples can be further improved to 7.4 pC N-1. Moreover, temperature-dependent resistivity measurements indicate that even at 1000 °C, the ceramics exhibit a high resistivity of 8.9 × 105 Ω cm. By combining X-ray diffraction, Raman spectra, transmission electron microscopy and piezoresponse force microscopy data, the enhanced piezoelectricity of the ceramics is attributed to local heterogeneity induced by Li/Ce doping. Our results unequivocally demonstrate the suitability of modified LTO ceramics for ultra-high-temperature piezoelectric applications.

CYP3A Mediates an Unusual C(sp2)-C(sp3) Bond Cleavage via Ipso-Addition of Oxygen in Drug Metabolism.

Mammalian cytochrome P450 drug-metabolizing enzymes rarely cleave carbon-carbon (C-C) bonds and the mechanisms of such cleavages are largely unknown. We identified two unusual cleavages of non-polar, unstrained C(sp2)-C(sp3) bonds in the FDA-approved tyrosine kinase inhibitor pexidartinib that are mediated by CYP3A4/5, the major human phase I drug metabolizing enzymes. Using a synthetic ketone, we rule out the Baeyer-Villiger oxidation mechanism that is commonly invoked to address P450-mediated C-C bond cleavages. Our studies in 18O2 and H2 18O enriched systems reveal two unusual distinct mechanisms of C-C bond cleavage: one bond is cleaved by CYP3A-mediated ipso-addition of oxygen to a C(sp2) site of N-protected pyridin-2-amines, and the other occurs by a pseudo-retro-aldol reaction after hydroxylation of a C(sp3) site. This is the first report of CYP3A-mediated C-C bond cleavage in drug metabolism via ipso-addition of oxygen mediated mechanism. CYP3A-mediated ipso-addition is also implicated in the regioselective C-C cleavages of several pexidartinib analogs. The regiospecificity of CYP3A-catalyzed oxygen ipso-addition under environmentally friendly conditions may be attractive and inspire biomimetic or P450-engineering methods to address the challenging task of C-C bond cleavages.