Clinical and genetic analysis of children with glucose transporter type 1 deficiency syndrome.

Glucose transporter type 1 deficiency syndrome (GLUT1-DS) is a rare metabolic encephalopathy with a wide variety of clinical phenotypes. In the present study, 15 patients diagnosed with GLUT1-DS were selected, all of whom had obvious clinical manifestations and complete genetic testing. Their clinical data and genetic reports were collated. All patients were provided with a ketogenic diet (KD) and an improvement in their symptoms was observed during a follow-up period of up to 1 year. The results revealed that the 15 cases had clinical symptoms, such as convulsions or dyskinesia. Although none had a cerebrospinal fluid/glucose ratio <0.4, the genetic report revealed that all had the solute carrier family 2 member 1 gene variant, and their clinical symptoms basically improved following the use of the KD. GLUT1-DS is a genetic metabolic disease that causes a series of neurological symptoms due to glucose metabolism disorders in the brain. Low glucose levels in cerebrospinal fluid and genetic testing are key diagnostic criteria, and the KD is a highly effective treatment option. By summarizing and analyzing patients with GLUT1-DS, summarizing clinical characteristics and expanding their gene profile, the findings of the present study may be of clinical significance for the early recognition and diagnosis of the disease, so as to conduct early treatment and shorten the duration of brain energy deficiency. This is of utmost importance for improving the prognosis and quality of life of affected children.

A bifunctional methyltransferase in biosynthesis of antitumor antibiotic streptonigrin.

Streptonigrin (STN, 1) is a highly functionalized aminoquinone alkaloid antibiotic with broad and potent antitumor activity. STN structurally contains four methyl groups belonging to two types: C-methyl group and O-methyl groups. Here, we report the biochemical characterization of the O-methyltransferase StnQ2 that can catalyze both the methylation of a hydroxyl group and a carboxyl group in the biosynthesis of streptonigrin. This work not only provides a new insight into methyltransferases, but also advances the elucidation of the complete biosynthetic pathway of streptonigrin.

Modulating Charge-Transfer Excited States of Multiple Resonance Emitters via Intramolecular Covalent Bond Locking.

Advanced multiple resonance thermally activated delayed fluorescence (MR-TADF) emitters with high efficiency and color purity have emerged as a research focus in developing ultra-high-definition displays. Herein, we disclose an approach to modulate charge-transfer excited states of MR emitters via intramolecular covalent bond locking. This strategy can promote the evolution of strong intramolecular charge transfer (ICT) states into weak ICT states, ultimately narrowing the full-width at half-maximum (FWHM) of emitters. To modulate the ICT intensity, two octagonal rings are introduced to yield molecule m-DCzDAz-BNCz. Compounds m-CzDAz-BNCz and m-DCzDAz-BNCz exhibit bright light-green and green fluorescence in toluene, with emission maxima of 504 and 513 nm, and FWHMs of 28 and 34 nm, respectively. Sensitized organic light-emitting diodes (OLEDs) employing emitters m-CzDAz-BNCz and m-DCzDAz-BNCz exhibit green emission with peaks of 508 and 520 nm, Commission Internationale de L'Eclairage (CIE) coordinates of (0.12, 0.65) and (0.19, 0.69), and maximum external quantum efficiencies (EQEs) of 30.2% and 32.6%, respectively.

Evaluation of Fatigue Behavior of Asphalt Field Cores Using Discrete Element Modeling.

Fatigue cracking is one of the primary distresses of asphalt pavements, which significantly affects the asphalt pavement performance. The fatigue behavior of the asphalt mixture observed in the laboratory test can vary depending on the type of fatigue test and the dimension and shape of the test specimen. The variations can make it difficult to accurately evaluate the fatigue properties of the field asphalt concrete. Accordingly, this study proposed a reliable method to evaluate the fatigue behavior of the asphalt field cores based on discrete element modeling (DEM). The mesoscopic geometric model was built using discrete element software PFC (Particle Flow Code) and CT scan images of the asphalt field cores. The virtual fatigue test was simulated in accordance with the semi-circular bending (SCB) test. The mesoscopic parameters of the contacting model in the virtual test were determined through the uniaxial compression dynamic modulus test and SCB test. Based on the virtual SCB test, the displacement, contact forces, and crack growth were analyzed. The test results show that the fatigue life simulated in the virtual test was consistent with that of the SCB fatigue test. The fatigue cracks in the asphalt mixture were observed in three stages, i.e., crack initiation, crack propagation, and failure. It was found that the crack propagation stage consumes a significant portion of the fatigue life since the tensile contact forces mainly increase in this stage.

Experimental Investigation of Water Vapor Concentration on Fracture Properties of Asphalt Concrete.

The effect of moisture on the fracture resistance of asphalt concrete is a significant concern in pavement engineering. To investigate the effect of the water vapor concentration on the fracture properties of asphalt concrete, this study first designed a humidity conditioning program at the relative humidity (RH) levels of 2%, 50%, 80%, and 100% for the three types of asphalt concrete mixtures (AC-13C, AC-20C, and AC-25C).The finite element model was developed to simulate the water vapor diffusion and determine the duration of the conditioning period. The semi-circular bending (SCB) test was then performed at varying temperatures of 5 °C, 15 °C, and 25 °C to evaluate the fracture energy and tensile strength of the humidity-conditioned specimens. The test results showed that the increasing temperature and the RH levels resulted in a lower peak load but greater displacement of the mixtures. Both the fracture energy and tensile strength tended to diminish with the rising temperature. It was also found that moisture had a significant effect on the tensile strength and fracture energy of asphalt concrete. Specifically, as the RH level increased from 2% to 100% (i.e., the water vapor concentration rose from 0.35 g/m3 to 17.27 g/m3), the tensile strength of the three types of mixtures was reduced by 34.84% on average, which revealed that the water vapor led to the loss of adhesion and cohesion within the mixture. The genetic expression programming (GEP) model was developed to quantify the effect of water vapor concentrations and temperature on the fracture indices.

PM10 exposure induces bronchial hyperresponsiveness by upreguating acetylcholine muscarinic 3 receptor.

Exposure to particulate matter (PM10) can induce respiratory diseases that are closely related to bronchial hyperresponsiveness. However, the involved mechanism remains to be fully elucidated. This study aimed to demonstrate the effects of PM10 on the acetylcholine muscarinic 3 receptor (CHRM3) expression and the role of the ERK1/2 pathway in rat bronchial smooth muscle. A whole-body PM10 exposure system was used to stimulate bronchial hyperresponsiveness in rats for 2 and 4 months, accompanied by MEK1/2 inhibitor U0126 injection. The whole-body plethysmography system and myography were used to detect the pulmonary and bronchoconstrictor function, respectively. The mRNA and protein levels were determined by Western blotting, qPCR, and immunofluorescence. Enzyme-linked immunosorbent assay was used to detect the inflammatory cytokines. Compared with the filtered air group, 4 months of PM10 exposure significantly increased CHRM3-mediated pulmonary function and bronchial constriction, elevated CHRM3 mRNA and protein expression levels on bronchial smooth muscle, then induced bronchial hyperreactivity. Additionally, 4 months of PM10 exposure caused an increase in ERK1/2 phosphorylation and increased the secretion of inflammatory factors in bronchoalveolar lavage fluid. Treatment with the MEK1/2 inhibitor, U0126 inhibited the PM10 exposure-induced phosphorylation of the ERK1/2 pathway, thereby reducing the PM10 exposure-induced upregulation of CHRM3 in bronchial smooth muscle and CHRM3-mediated bronchoconstriction. U0126 could rescue PM10 exposure-induced pathological changes in the bronchus. In conclusion, PM10 exposure can induce bronchial hyperresponsiveness in rats by upregulating CHRM3, and the ERK1/2 pathway may be involved in this process. These findings could reveal a potential therapeutic target for air pollution induced respiratory diseases.

Hotspots and Global Trends of Nursing Research on Mobile Applications in Nursing From 2012 to 2023: A Bibliometric Analysis.

The rapid integration of mobile applications in healthcare has prompted an evolutionary change in nursing domain. This study aimed to systematically analyze the basic publication characteristics, research priorities, emerging trends, and thematic evolutions concerning mobile applications in nursing, providing an overview of the field's developmental trajectory and future directions. This was a descriptive bibliometric study. Data were collected on July 5, 2023, from the Web of Science database and analyzed by using the Bibliometrix package in R software. The search strategy yielded 417 documents authored by 1969 researchers, cited 12 595 references, and featured 1213 author keywords, spanning from 2012 to 2023. Research on mobile applications in nursing exhibited several key trends: (1) substantial collaboration among authors; (2) significant growth in the number of publications; (3) self-management was the most prominent hot topic; and (4) an evolution of research themes from general topics to a more specific focus on people-centered and problem-centered research. The corpus of literature pertaining to research on mobile applications within the nursing domain is anticipated to expand continually. Future research and practice in the nursing field are expected to benefit significantly from multidisciplinary collaboration and advancements in emerging technologies, including artificial intelligence.

Effects of Fe(III) on the formation and toxicity alteration of halonitromethanes, dichloroacetonitrile, and dichloroacetamide from polyethyleneimine during UV/chlorine disinfection.

Trace iron ions (Fe(III)) are commonly found in water and wastewater, where free chlorine is very likely to coexist with Fe(III) affecting the disinfectant's stability and N-DBPs' fate during UV/chlorine disinfection, and yet current understanding of these mechanisms is limited. This study investigates the effects of Fe(III) on the formation and toxicity alteration of halonitromethanes (HNMs), dichloroacetonitrile (DCAN), and dichloroacetamide (DCAcAm) from polyethyleneimine (PEI) during UV/chlorine disinfection. Results reveal that the maxima concentrations of HNMs, DCAN, and DCAcAm during UV/chlorine disinfection with additional Fe(III) were 1.39, 1.38, and 1.29 times higher than those without additional Fe(III), instead of being similar to those of Fe(III) inhibited the formation of HNMs, DCAN and DCAcAm during chlorination disinfection. Meanwhile, higher Fe(III) concentration, acidic pH, and higher chlorine dose were more favorable for forming HNMs, DCAN, and DCAcAm during UV/chlorine disinfection, which were highly dependent on the involvement of HO· and Cl·. Fe(III) in the aquatic environment partially hydrolyzed to the photoactive Fe(III)­hydroxyl complexes Fe(OH)2+ and [Fe(H2O)6]3+, which undergone UV photoactivation and coupling reactions with HOCl to achieve effective Fe(III)/Fe(II) interconversion, a process that facilitated the sustainable production of HO·. Extensive product analysis and comparison verified that the HO· production enhanced by the Fe(III)/Fe(II) internal cycle played a primary role in increasing HNMs, DCAN, and DCAcAm productions during UV/chlorine disinfection. Note that the incorporation of Fe(III) increased the cytotoxicity and genotoxicity of HNMs, DCAN, and DCAcAm formed during UV/chlorine disinfection, and yet Fe(III) did not have a significant effect on the acute toxicity of water samples before, during, and after UV/chlorine disinfection. The new findings broaden the knowledge of Fe(III) affecting HNMs, DCAN, and DCAcAm formation and toxicity alteration during UV/chlorine disinfection.

A prominent role of LncRNA H19 in H. pylori CagA induced DNA damage response and cell malignancy.

Helicobacter pylori (H. pylori), together with its CagA, has been implicated in causing DNA damage, cell cycle arrest, apoptosis, and the development of gastric cancer. Although lncRNA H19 is abundantly expressed in gastric cancer and functions as a pro-oncogene, it remains unclear whether lncRNA H19 contributes to the oncogenic process of H. pylori CagA. This study investigates the role of H19 in the DNA damage response and malignancy induced by H. pylori. It was observed that cells infected with CagA+ H. pylori strain (GZ7/cagA) showed significantly higher H19 expression, resulting in increased γH2A.X and p-ATM expression and decreased p53 and Rad51 expression. Faster cell migration and invasion was also observed, which was reversed by H19 knockdown in H. pylori. YWHAZ was identified as an H19 target protein, and its expression was increased in H19 knockdown cells. GZ7/cagA infection responded to the increased YWHAZ expression induced by H19 knockdown. In addition, H19 knockdown stimulated cells to enter the G2-phase and attenuated the effect of GZ7/cagA infection on the cellular S-phase barrier. The results suggest that H. pylori CagA can upregulate H19 expression, participate in the DNA damage response and promote cell migration and invasion, and possibly affect cell cycle arrest via regulation of YWHAZ.

Diversity and saline-alkali resistance of Coleoptera endosymbiont bacteria in arid and semi-arid climate.

Soil salinization usually occurs in arid and semi-arid climate areas from 37 to 50 degrees north latitude and 73 to 123 degrees east longitude. These regions are inhabited by a large number of Coleopteran insects, which play an important role in the ecological cycle. However, little is known about the endosymbiotic microbial taxa and their biological characteristics in these insects. A study of endosymbiotic microorganisms of Coleoptera from Xinjiang, a typical arid and inland saline area, revealed that endosymbiont bacteria with salinity tolerance are common among the endosymbionts of Coleoptera. Functional prediction of the microbiota analysis indicated a higher abundance of inorganic ion transporters and metabolism in these endosymbiont strains. Screening was conducted on the tolerable 11% NaCl levels of Brevibacterium casei G20 (PRJNA754761), and differential metabolite and proteins were performed. The differential metabolites of the strain during the exponential and plateau phases were found to include benzene compounds, organic acids, and their derivatives. These results suggest that the endosymbiotic microorganisms of Coleoptera in this environment have adaptive evolution to extreme environments, and this group of microorganisms is also one of the important resources for mining saline and alkaline-tolerant chassis microorganisms and high-robustness enzymes. IMPORTANCE: Coleoptera insects, as the first largest order of insect class, have the characteristics of a wide variety and wide distribution. The arid and semi-arid climate makes it more adaptable. By studying the endosymbiont bacteria of Coleoptera insects, we can systematically understand the adaptability of endosymbiont bacteria to host and special environment. Through the analysis of endosymbiont bacteria of Coleoptera insects in different saline-alkali areas in arid and semi-arid regions of Xinjiang, it was found that bacteria in different host samples were resistant to saline-alkali stress. These results suggest that bacteria and their hosts co-evolved in response to this climate. Therefore, this study is of great significance for understanding the endosymbiont bacteria of Coleoptera insects and obtaining extremophile resources (Saline-alkali-resistant chassis strains with modification potential for the production of bulk chemicals and highly robust industrial enzymes).

Novel therapeutic regimens against Helicobacter pylori: an updated systematic review.

Helicobacter pylori (H. pylori) is a strict microaerophilic bacterial species that exists in the stomach, and H. pylori infection is one of the most common chronic bacterial infections affecting humans. Eradicating H. pylori is the preferred method for the long-term prevention of complications such as chronic gastritis, peptic ulcers, gastric mucosa-associated lymphoid tissue lymphoma, and gastric cancer. However, first-line treatment with triple therapy and quadruple therapy has been unable to cope with increasing antibacterial resistance. To provide an updated review of H. pylori infections and antibacterial resistance, as well as related treatment options, we searched PubMed for articles published until March 2024. The key search terms were "H. pylori", "H. pylori infection", "H. pylori diseases", "H. pylori eradication", and "H. pylori antibacterial resistance." Despite the use of antimicrobial agents, the annual decline in the eradication rate of H. pylori continues. Emerging eradication therapies, such as the development of the new strong acid blocker vonoprazan, probiotic adjuvant therapy, and H. pylori vaccine therapy, are exciting. However, the effectiveness of these treatments needs to be further evaluated. It is worth mentioning that the idea of altering the oxygen environment in gastric juice for H. pylori to not be able to survive is a hot topic that should be considered in new eradication plans. Various strategies for eradicating H. pylori, including antibacterials, vaccines, probiotics, and biomaterials, are continuously evolving. A novel approach involving the alteration of the oxygen concentration within the growth environment of H. pylori has emerged as a promising eradication strategy.

Organocatalytic Csp2-O Amination of Quinolin-4(1H)-ones with 3-Alkynyl-3-hydroxyisoindolinones.

The Brønsted acid catalytic Csp2-O amination of quinolin-4(1H)-ones with 3-alkynyl-3-hydroxyisoindolinones as animation reagents has been developed. The cascade dehydration/conjugate addition/intramolecular annulation/ring-opening reaction proceeded smoothly to afford a broad scope of aminated products with high efficiency. Furthermore, the enantioselective construction of Csp2-N atropisomers was also investigated in the presence of chiral phosphoric acid. Importantly, this work not only realized the organocatalytic Csp2-O amination of quinolin-4(1H)-ones but also laid the foundation for directly asymmetric synthesis of Csp2-N atropisomers.

Systems Genetics Analyses Reveals Key Genes Related to Behavioral Traits in the Striatum of CFW Mice.

The striatum plays a central role in directing many complex behaviors ranging from motor control to action choice and reward learning. In our study, we used 55 male CFW mice with rapid decay linkage disequilibrium to systematically mine the striatum-related behavioral functional genes by analyzing their striatal transcriptomes and 79 measured behavioral phenotypic data. By constructing a gene coexpression network, we clustered the genes into 13 modules, with most of them being positively correlated with motor traits. Based on functional annotations as well as Fisher's exact and hypergeometric distribution tests, brown and magenta modules were identified as core modules. They were significantly enriched for striatal-related functional genes. Subsequent Mendelian randomization analysis verified the causal relationship between the core modules and dyskinesia. Through the intramodular gene connectivity analysis, Adcy5 and Kcnma1 were identified as brown and magenta module hub genes, respectively. Knock outs of both Adcy5 and Kcnma1 lead to motor dysfunction in mice, and KCNMA1 acts as a risk gene for schizophrenia and smoking addiction in humans. We also evaluated the cellular composition of each module and identified oligodendrocytes in the striatum to have a positive role in motor regulation.

Tannic acid and quaternized chitosan mediated puerarin-loaded octacalcium phosphate /sodium alginate scaffold for bone tissue engineering.

Current limitations in mechanical performance and foreign body reactions (FBR) often lead to implant failure, restricting the application of bioceramic scaffolds. This study presents a novel 3D-printed scaffold that combines the release of anti-inflammatory drugs with osteogenic stimulation. Initially, the inorganic and organic phases were integrated to ensure the scaffold's mechanical integrity through catechol chemistry and the electrostatic interactions between tannic acid and quaternary ammonium chitosan. Subsequently, layers of polydopamine-encapsulated puerarin-loaded zeolitic imidazolate framework-8 (ZIF-8) were self-assembled onto the stent's surface, creating the drug-loaded scaffold that improved drug release without altering the scaffold's structure. Compared with unloaded scaffolds, the puerarin-loaded scaffold demonstrated excellent osteogenic differentiation properties along with superior anti-inflammatory and osteogenic effects in a range of in vitro and in vivo studies. RNA sequencing clarified the role of the TNF and NF/κB signaling pathways in these effects, further supporting the scaffold's osteogenic potential. This study introduces a novel approach for creating drug-loaded scaffolds, providing a unique method for treating cancellous bone defects.

Association of physical activity pattern and risk of Parkinson's disease.

Increasing evidence suggests an association between exercise duration and Parkinson's disease. However, no high-quality prospective evidence exists confirming whether differences exist between the two modes of exercise, weekend warrior and equal distribution of exercise duration, and Parkinson's risk. Hence, this study aimed to explore the association between different exercise patterns and Parkinson's risk using exercise data from the UK Biobank. The study analyzed data from 89,400 UK Biobank participants without Parkinson's disease. Exercise data were collected using the Axivity AX3 wrist-worn triaxial accelerometer. Participants were categorized into three groups: inactive, regularly active, and engaged in the weekend warrior (WW) pattern. The relationship between these exercise patterns and Parkinson's risk was assessed using a multifactorial Cox model. During a mean follow-up of 12.32 years, 329 individuals developed Parkinson's disease. In a multifactorial Cox model, using the World Health Organization-recommended threshold of 150 min of moderate-to-vigorous physical activity per week, both the active WW group [hazard ratio (HR) = 0.58; 95% confidence interval (CI) = 0.43-0.78; P < 0.001] and the active regular group (HR = 0.44; 95% CI = 0.34-0.57; P < 0.001) exhibited a lower risk of developing Parkinson's disease compared with the inactive group. Further, no statistically significant difference was observed between the active WW and the active regular groups (HR = 0.77; 95% CI = 0.56-1.05; P = 0.099). In conclusion, in this cohort study, both the WW exercise pattern and an equal distribution of exercise hours were equally effective in reducing Parkinson's risk.

Formation and toxicity alteration of halonitromethanes from Chlorella vulgaris during UV/chloramination process involving bromide ion.

Frequent algal blooms cause algal cells and their algal organic matter (AOM) to become critical precursors of disinfection by-products (DBPs) during water treatment. The presence of bromide ion (Br-) in water has been demonstrated to affect the formation laws and species distribution of DBPs. However, few researchers have addressed the formation and toxicity alteration of halonitromethanes (HNMs) from algae during disinfection in the presence of Br-. Therefore, in this work, Chlorella vulgaris was selected as a representative algal precursor to investigate the formation and toxicity alteration of HNMs during UV/chloramination involving Br-. The results showed that the formation concentration of HNMs increased and then decreased during UV/chloramination. The intracellular organic matter of Chlorella vulgaris was more susceptible to form HNMs than the extracellular organic matter. When the Br-: Cl2 mass ratio was raised from 0.004 to 0.08, the peak of HNMs total concentration increased 33.99%, and the cytotoxicity index and genotoxicity index of HNMs increased 67.94% and 22.80%. Besides, the formation concentration and toxicity of HNMs increased with increasing Chlorella vulgaris concentration but decreased with increasing solution pH. Possible formation pathways of HNMs from Chlorella vulgaris during UV/chloramination involving Br- were proposed based on the alteration of nitrogen species and fluorescence spectrum analysis. Furthermore, the formation laws of HNMs from Chlorella vulgaris in real water samples were similar to those in deionized water samples. This study contributes to a better comprehension of HNMs formation from Chlorella vulgaris and provides valuable information for water managers to reduce hazards associated with the formation of HNMs.

Prognostic Significance of Excision Repair Cross-Complementation Group 1 on Circulating Tumor Cells for Nasopharyngeal Carcinoma.

BACKGROUND: Liquid biopsy, including the detection of circulating tumor cells (CTCs), has emerged as a promising tool for cancer diagnosis and monitoring. However, the prognostic value of CTCs in nasopharyngeal carcinoma (NPC) remains unclear due to the lack of phenotypic characterization. The expression of Excision Repair Cross-Complementation Group 1 (ERCC1) and CTCs epithelial-mesenchymal transition (EMT) have been associated with treatment efficacy. In this study, we aimed to evaluate the prognostic significance of ERCC1 expression on CTCs and their EMT subtypes before treatment in NPC. METHODS: We retrospectively analyzed 108 newly diagnosed locally advanced NPC patients who underwent CanPatrol™ CTC testing between November 2018 and November 2021. CTCs were counted and classified into epithelial, epithelial-mesenchymal hybrid, and mesenchymal subtypes. ERCC1 expression was divided into negative and positive groups. Clinical features and survival outcomes were analyzed. RESULTS: The positive rate of CTCs was 92.6% (100/108), with an ERCC1 positivity rate of 74% (74/100). Further analysis of the subtypes showed that positive ERCC1 on mesenchymal CTCs was associated with a later N stage (P = .01). Positive ERCC1 expression was associated with poor overall survival (OS; P = .039) and disease-free survival (DFS; P = .035). Further analysis of subtypes showed that the positive ERCC1 on mesenchymal-type CTCs was associated with poor OS (P = .012) and metastasis-free survival (MFS; P = .001). CONCLUSION: Our findings suggest that ERCC1 expression on CTCs may serve as a new prognostic marker for NPC patients. Evaluating CTCs subtypes may become an auxiliary tool for personalized and precise treatment.

BackgroundLiquid biopsy, including the detection of circulating tumor cells (CTCs), has emerged as a promising tool for cancer diagnosis and monitoring. However, the prognostic value of CTCs in nasopharyngeal carcinoma (NPC) remains unclear due to the lack of phenotypic characterization. The expression of Excision Repair Cross-Complementation Group 1 (ERCC1) and CTCs epithelial-mesenchymal transition (EMT) have been associated with treatment efficacy. In this study, we aimed to evaluate the prognostic significance of ERCC1 expression on CTCs and their EMT subtypes before treatment in NPC.MethodsWe retrospectively analyzed 108 newly diagnosed locally advanced NPC patients who underwent CanPatrol™ CTC testing between November 2018 and November 2021. CTCs were counted and classified into epithelial, epithelial-mesenchymal hybrid, and mesenchymal subtypes. ERCC1 expression was divided into negative and positive groups. Clinical features and survival outcomes were analyzed.ResultsThe positive rate of CTCs was 92.6% (100/108), with an ERCC1 positivity rate of 74% (74/100). Further analysis of the subtypes showed that positive ERCC1 on mesenchymal CTCs was associated with a later N stage (P = .01). Positive ERCC1 expression was associated with poor overall survival (OS; P = .039) and disease-free survival (DFS; P = .035). Further analysis of subtypes showed that the positive ERCC1 on mesenchymal-type CTCs was associated with poor OS (P = .012) and metastasis-free survival (MFS; P = .001).ConclusionOur findings suggest that ERCC1 expression on CTCs may serve as a new prognostic marker for NPC patients. Evaluating CTCs subtypes may become an auxiliary tool for personalized and precise treatment.

Effect of temperature on anisotropic bending elasticity of dsRNA: an all-atom molecular dynamics simulation.

Employing all-atom molecular dynamics simulations, we examined the temperature-dependent behavior of bending elasticity in double-stranded RNA (dsRNA). Specifically, we focused on the bending persistence length and its constituent components, namely, the tilt and roll stiffness. Our results revealed a near-linear decrease in these stiffness components as a function of temperature, thereby highlighting the increased flexibility of dsRNA at elevated temperatures. Furthermore, our data revealed a significant anisotropy in dsRNA bending elasticity, which diminished with increasing temperature, attributable to marked disparities in tilt and roll stiffness components. We delineated the underlying biophysical mechanisms and corroborated our findings with extant literature. These observations offer salient implications for advancing our understanding of nucleic acid elasticity, and are pertinent to potential medical applications.

Early-life tobacco smoke exposure and stroke risk: a prospective study of 341,783 and 352,737 UK Biobank participants.

INTRODUCTION: Stroke is a life-threatening condition that causes a major medical burden globally. The currently used methods for the prevention or prediction of stroke have certain limitations. Exposure to tobacco in early life, including smoking during adolescence and maternal smoking during pregnancy, can affect adolescent development and lead to several negative outcomes. However, the association between early-life tobacco exposure and stroke is not known. METHODS: In this prospective cohort study, for the analyses involving exposure to maternal smoking during pregnancy and age of smoking initiation, we included 304,984 and 342,893 participants, respectively., respectively from the UK Biobank. Cox proportional hazard regression model and subgroup analyses were performed to investigate the association between early-life tobacco exposure and stroke. Mediation analyses were performed to identify the mediating role of biological aging in the association between early tobacco exposure and stroke. RESULTS: Compared with participants whose mothers did not smoke during pregnancy, participants whose mothers smoked during pregnancy showed an 11% increased risk of stroke (HR: 1.11, 95% CI: 1.05-1.18, P < 0.001). Compared with participants who never smoked, participants who smoked during adulthood, adolescence and childhood showed a 22%, 24%, and 38% increased risk of stroke during their adulthood, respectively. Mediation analysis indicated that early-life tobacco exposure can cause stroke by increasing biological aging. CONCLUSION: This study reveals that exposure to tobacco during early life is associated with an increased risk of experiencing a stroke, and increased biological aging can be the underlying mechanism.

Cytochrome P450 Mining for Bufadienolide Diversification.

Bufadienolides are a class of steroids with a distinctive α-pyrone ring at C17, mostly produced by toads and consisting of over 100 orthologues. They exhibit potent cardiotonic and antitumor activities and are active ingredients of the traditional Chinese medicine Chansu and Cinobufacini. Direct extraction from toads is costly, and chemical synthesis is difficult, limiting the accessibility of active bufadienolides with diverse modifications and trace content. In this work, based on the transcriptome and genome analyses, using a yeast-based screening platform, we obtained eight cytochrome P450 (CYP) enzymes from toads, which catalyze the hydroxylation of bufalin and resibufogenin at different sites. Moreover, a reported fungal CYP enzyme Sth10 was found functioning in the modification of bufalin and resibufogenin at multiple sites. A total of 15 bufadienolides were produced and structurally identified, of which six were first discovered. All of the compounds were effective in inhibiting the proliferation of tumor cells, especially 19-hydroxy-bufalin (2) and 1ß-hydroxy-bufalin (3), which were generated from bufalin hydroxylation catalyzed by CYP46A35. The catalytic efficiency of CYP46A35 was improved about six times and its substrate diversity was expanded to progesterone and testosterone, the common precursors for steroid drugs, achieving their efficient and site-specific hydroxylation. These findings elucidate the key modification process in the synthesis of bufadienolides by toads and provide an effective way for the synthesis of unavailable bufadienolides with site-specific modification and active potentials.