Ultrasound-responsive theranostic platform for the timely monitoring and efficient thrombolysis in thrombi of tPA resistance.

There is no effective and noninvasive solution for thrombolysis because the mechanism by which certain thrombi become tissue plasminogen activator (tPA)-resistant remains obscure. Endovascular thrombectomy is the last option for these tPA-resistant thrombi, thus a new noninvasive strategy is urgently needed. Through an examination of thrombi retrieved from stroke patients, we found that neutrophil extracellular traps (NETs), ε-(γ-glutamyl) lysine isopeptide bonds and fibrin scaffolds jointly comprise the key chain in tPA resistance. A theranostic platform is designed to combine sonodynamic and mechanical thrombolysis under the guidance of ultrasonic imaging. Breakdown of the key chain leads to a recanalization rate of more than 90% in male rat tPA-resistant occlusion model. Vascular reconstruction is observed one month after recanalization, during which there was no thrombosis recurrence. The system also demonstrates noninvasive theranostic capabilities in managing pigs' long thrombi (>8 mm) and in revascularizing thrombosis-susceptible tissue-engineered vascular grafts, indicating its potential for clinical application. Overall, this noninvasive theranostic platform provides a new strategy for treating tPA-resistant thrombi.

Clinical characteristics and complication risks in data-driven clusters among Chinese community diabetes populations.

BACKGROUND: Novel diabetes phenotypes were proposed by the Europeans through cluster analysis, but Chinese community diabetes populations might exhibit different characteristics. This study aims to explore the clinical characteristics of novel diabetes subgroups under data-driven analysis in Chinese community diabetes populations. METHODS: We used K-means cluster analysis in 6369 newly diagnosed diabetic patients from eight centers of the REACTION (Risk Evaluation of cAncers in Chinese diabeTic Individuals) study. The cluster analysis was performed based on age, body mass index, glycosylated hemoglobin, homeostatic modeled insulin resistance index, and homeostatic modeled pancreatic ß-cell functionality index. The clinical features were evaluated with the analysis of variance (ANOVA) and chi-square test. Logistic regression analysis was done to compare chronic kidney disease and cardiovascular disease risks between subgroups. RESULTS: Overall, 2063 (32.39%), 658 (10.33%), 1769 (27.78%), and 1879 (29.50%) populations were assigned to severe obesity-related and insulin-resistant diabetes (SOIRD), severe insulin-deficient diabetes (SIDD), mild age-associated diabetes mellitus (MARD), and mild insulin-deficient diabetes (MIDD) subgroups, respectively. Individuals in the MIDD subgroup had a low risk burden equivalent to prediabetes, but with reduced insulin secretion. Individuals in the SOIRD subgroup were obese, had insulin resistance, and a high prevalence of fatty liver, tumors, family history of diabetes, and tumors. Individuals in the SIDD subgroup had severe insulin deficiency, the poorest glycemic control, and the highest prevalence of dyslipidemia and diabetic nephropathy. Individuals in MARD subgroup were the oldest, had moderate metabolic dysregulation and the highest risk of cardiovascular disease. CONCLUSION: The data-driven approach to differentiating the status of new-onset diabetes in the Chinese community was feasible. Patients in different clusters presented different characteristics and risks of complications.

Remnant cholesterol is more positively related to diabetes, prediabetes, and insulin resistance than conventional lipid parameters and lipid ratios: A multicenter, large sample survey.

BACKGROUND: Not many large-sample investigations are available that compare the potency of the relationship of remnant cholesterol (RC) and other lipid parameters with diabetes and prediabetes. The goals of our study are to discover the relationship between RC and prediabetes, diabetes, and insulin resistance (IR) and to investigate RC, high-density lipoprotein cholesterol (HDL-C), non-HDL-C, triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), TC/HDL-C, LDL-C/HDL-C, and TG/HDL-C, which are the lipid parameters that are most positively related to diabetes, prediabetes, and IR. METHODS: This research enrolled 36 684 subjects from China's eight provinces. We employed multiple logistic regression analysis for testing the relationship between lipid parameters and diabetes, prediabetes, and IR. RESULTS: After adjusting for potential confounders, and comparing the results with other lipid parameters, the positive relationship between RC and diabetes (odds ratio [OR] 1.417, 95% confidence interval [CI]: 1.345-1.492), prediabetes (OR 1.555, 95% CI: 1.438-1.628), and IR (OR 1.488, 95% CI: 1.404-1.577) was highest. RC was still related to diabetes, prediabetes, and IR even when TG <2.3 mmol/L (diabetes: OR 1.256, 95% CI: 1.135-1.390; prediabetes: OR 1.503, 95% CI: 1.342-1.684; and IR: OR 1.278, 95% CI: 1.140-1.433), LDL-C <2.6 mmol/L (diabetes: OR 1.306, 95% CI: 1.203-1.418; prediabetes: OR 1.597, 95% CI: 1.418-1.798; and IR: OR 1.552, 95% CI: 1.416-1.701), or HDL-C ≥1 mmol/L (diabetes: OR 1.456, 95% CI: 1.366-1.550; prediabetes: OR 1.553, 95% CI: 1.421-1.697; and IR: OR 1.490, 95% CI: 1.389-1.598). CONCLUSION: RC is more positively related to diabetes, prediabetes, and IR than conventional lipids and lipid ratios in the general population, the relationships between RC and diabetes, prediabetes, and IR are stable, even if HDL-C, LDL-C, or TG are at appropriate levels.

VolcanoSV enables accurate and robust structural variant calling in diploid genomes from single-molecule long read sequencing.

Structural variants (SVs) significantly contribute to human genome diversity and play a crucial role in precision medicine. Although advancements in single-molecule long-read sequencing offer a groundbreaking resource for SV detection, identifying SV breakpoints and sequences accurately and robustly remains challenging. We introduce VolcanoSV, an innovative hybrid SV detection pipeline that utilizes both a reference genome and local de novo assembly to generate a phased diploid assembly. VolcanoSV uses phased SNPs and unique k-mer similarity analysis, enabling precise haplotype-resolved SV discovery. VolcanoSV is adept at constructing comprehensive genetic maps encompassing SNPs, small indels, and all types of SVs, making it well-suited for human genomics studies. Our extensive experiments demonstrate that VolcanoSV surpasses state-of-the-art assembly-based tools in the detection of insertion and deletion SVs, exhibiting superior recall, precision, F1 scores, and genotype accuracy across a diverse range of datasets, including low-coverage (10x) datasets. VolcanoSV outperforms assembly-based tools in the identification of complex SVs, including translocations, duplications, and inversions, in both simulated and real cancer data. Moreover, VolcanoSV is robust to various evaluation parameters and accurately identifies breakpoints and SV sequences.

Synergistic pectin deconstruction is a prerequisite for mutualistic interactions between honeybee gut bacteria.

The honeybee gut microbiome is crucial for degrading diverse pollen glycans. Yet it is unclear how this process shapes the interactions among bacteria. Here, we demonstrate a conditional mutualistic interaction between strains of two honeybee gut bacteria Bifidobacterium asteroides and Gilliamella apicola. When co-occurring in vitro and in vivo, Bifidobacterium provides complementary demethylation service to promote Gilliamella growth on methylated homogalacturonan, an enriched polysaccharide of pectin. In exchange, Gilliamella shares digestive products with Bifidobacterium, through which a positive interaction is established. This positive interaction vanishes when Bifidobacterium is not required on a non-methylated diet. Results from biochemical and gene expression analyses combined with model simulation further suggest that the ratio change of the two major homogalacturonan breakdown products, galacturonic acid (GalA) and di-GalA, determines the bacterial interaction. This study unravels how glycan metabolism may shape the interactions between honeybee gut bacteria.

The genomic basis of childhood T-lineage acute lymphoblastic leukaemia.

T-lineage acute lymphoblastic leukaemia (T-ALL) is a high-risk tumour1 that has eluded comprehensive genomic characterization, which is partly due to the high frequency of noncoding genomic alterations that result in oncogene deregulation2,3. Here we report an integrated analysis of genome and transcriptome sequencing of tumour and remission samples from more than 1,300 uniformly treated children with T-ALL, coupled with epigenomic and single-cell analyses of malignant and normal T cell precursors. This approach identified 15 subtypes with distinct genomic drivers, gene expression patterns, developmental states and outcomes. Analyses of chromatin topology revealed multiple mechanisms of enhancer deregulation that involve enhancers and genes in a subtype-specific manner, thereby demonstrating widespread involvement of the noncoding genome. We show that the immunophenotypically described, high-risk entity of early T cell precursor ALL is superseded by a broader category of 'early T cell precursor-like' leukaemia. This category has a variable immunophenotype and diverse genomic alterations of a core set of genes that encode regulators of hematopoietic stem cell development. Using multivariable outcome models, we show that genetic subtypes, driver and concomitant genetic alterations independently predict treatment failure and survival. These findings provide a roadmap for the classification, risk stratification and mechanistic understanding of this disease.

Detecting biomarkers by dynamic nuclear polarization enhanced magnetic resonance.

Hyperpolarization stands out as a technique capable of significantly enhancing the sensitivity of nuclear magnetic resonance (NMR) and magnetic resonance imaging (MRI). Dynamic nuclear polarization (DNP), among various hyperpolarization methods, has gained prominence for its efficacy in real-time monitoring of metabolism and physiology. By administering a hyperpolarized substrate through dissolution DNP (dDNP), the biodistribution and metabolic changes of the DNP agent can be visualized spatiotemporally. This approach proves to be a distinctive and invaluable tool for non-invasively studying cellular metabolism in vivo, particularly in animal models. Biomarkers play a pivotal role in influencing the growth and metastasis of tumor cells by closely interacting with them, and accordingly detecting pathological alterations of these biomarkers is crucial for disease diagnosis and therapy. In recent years, a range of hyperpolarized DNP molecular bioresponsive agents utilizing various nuclei, such as 13C, 15N, 31P, 89Y, etc., have been developed. In this context, we explore how these magnetic resonance signals of nuclear spins enhanced by DNP respond to biomarkers, including pH, metal ions, enzymes, or redox processes. This review aims to offer insights into the design principles of responsive DNP agents, target selection, and the mechanisms of action for imaging. Such discussions aim to propel the future development and application of DNP-based biomedical imaging agents.

Symmetric optical multipass matrix systems and the general rapid design methodology.

We proposed an original type of multipass cell named symmetric optical multipass matrix system (SMMS), in which the same matrix patterns of various sizes can be formed on both sides. According to its special symmetric configurations, the SMMS design problem is modeled as a variant of the classical traveling salesman problem, which can be rapidly solved by evolutionary optimization algorithms. Two sets of 3-mirror SMMSs are designed, analyzed and built, which show superior characteristics of high stability, desirable beam quality and adjustable optical path lengths. Additionally, they can support simultaneous detection of multiple species with multi-laser channels. The proposed method is further extended to design a 4-mirror SMMS, which verifies the universality and robustness of the design methodology. The experimental observations are in consistent with the theoretical calculations. The newly proposed SMMSs have a broad application prospect in trace gas measurement.

Ultrasonic-assisted Fenton reaction inducing surface reconstruction endows nickel/iron-layered double hydroxide with efficient water and organics electrooxidation.

Nickel/iron-layered double hydroxide (NiFe-LDH) tends to undergo an electrochemically induced surface reconstruction during the water oxidation in alkaline, which will consume excess electric energy to overcome the reconstruction thermodynamic barrier. In the present work, a novel ultrasonic wave-assisted Fenton reaction strategy is employed to synthesize the surface reconstructed NiFe-LDH nanosheets cultivated directly on Ni foam (NiFe-LDH/NF-W). Morphological and structural characterizations reveal that the low-spin states of Ni2+ (t2g6eg2) and Fe2+ (t2g4eg2) on the NiFe-LDH surface partially transform into high-spin states of Ni3+ (t2g6eg1) and Fe3+ (t2g3eg2) and formation of the highly active species of NiFeOOH. A lower surface reconstruction thermodynamic barrier advantages the electrochemical process and enables the NiFe-LDH/NF-W electrode to exhibit superior electrocatalytic water oxidation activity, which delivers 10 mA cm-2 merely needing an overpotential of 235 mV. Besides, surface reconstruction endows NiFe-LDH/NF-W with outstanding electrooxidation activities for organic molecules of methanol, ethanol, glycerol, ethylene glycol, glucose, and urea. Ultrasonic-assisted Fenton reaction inducing surface reconstruction strategy will further advance the utilization of NiFe-LDH catalyst in water and organics electrooxidation.

Nonlinear dynamics of multi-omics profiles during human aging.

Aging is a complex process associated with nearly all diseases. Understanding the molecular changes underlying aging and identifying therapeutic targets for aging-related diseases are crucial for increasing healthspan. Although many studies have explored linear changes during aging, the prevalence of aging-related diseases and mortality risk accelerates after specific time points, indicating the importance of studying nonlinear molecular changes. In this study, we performed comprehensive multi-omics profiling on a longitudinal human cohort of 108 participants, aged between 25 years and 75 years. The participants resided in California, United States, and were tracked for a median period of 1.7 years, with a maximum follow-up duration of 6.8 years. The analysis revealed consistent nonlinear patterns in molecular markers of aging, with substantial dysregulation occurring at two major periods occurring at approximately 44 years and 60 years of chronological age. Distinct molecules and functional pathways associated with these periods were also identified, such as immune regulation and carbohydrate metabolism that shifted during the 60-year transition and cardiovascular disease, lipid and alcohol metabolism changes at the 40-year transition. Overall, this research demonstrates that functions and risks of aging-related diseases change nonlinearly across the human lifespan and provides insights into the molecular and biological pathways involved in these changes.

Molecular dynamics simulations of microscopic structural transition and macroscopic mechanical properties of magnetic gels.

Magnetic gels with embedded micro-/nano-sized magnetic particles in cross-linked polymer networks can be actuated by external magnetic fields, with changes in their internal microscopic structures and macroscopic mechanical properties. We investigate the responses of such magnetic gels to an external magnetic field, by means of coarse-grained molecular dynamics simulations. We find that the dynamics of magnetic particles are determined by the interplay of magnetic dipole-dipole interactions, polymer elasticity, and thermal fluctuations. The corresponding microscopic structures formed by the magnetic particles, such as elongated chains, can be controlled by the external magnetic field. Furthermore, the magnetic gels can exhibit reinforced macroscopic mechanical properties, where the elastic modulus increases algebraically with the magnetic moments of the particles in the form of ∝(m-mc)2 when magnetic chains are formed. This simulation work can not only serve as a tool for studying the microscopic and the macroscopic responses of the magnetic gels, but also facilitate future fabrications and practical controls of magnetic composites with desired physical properties.

Abundance, characteristics and ecological risk assessment of microplastics in ship ballast water in ports around Liaodong Peninsula, China.

The development of the shipping industry has led to a large volume of ballast water discharge annually. This accelerates pollutants' transfer and dispersion, such as microplastics. Currently, empirical data on microplastics in ballast water are rarely available. This study innovatively investigated the abundance, morphological characteristics (particle size, shape, and color), and polymer composition of microplastics in ballast water from ports surrounding the Liaodong Peninsula. The results revealed that the average abundance of microplastics in 13 ships' ballast water was 6071.30 ± 1313.85 items/m3. Notably, the small microplastics (0.06-2.50 mm) were most abundant, accounting for 94.52 % of the total microplastics. Transparent, fiber, and polyethylene glycol terephthalate were the most prevalent color, shape, and polymer composition of microplastics detected in the ballast water. The risk assessment indicated that these microplastics present ecological risks to organisms. These findings suggest that ship ballast water is the potential "hotspot" for marine microplastics transport.

Pt Single Atoms Loaded on Thin-Layer TiO2 Electrodes: Electrochemical and Photocatalytic Features.

Recently, the use of Pt in the form of single atoms (SA) has attracted considerable attention to promote the cathodic hydrogen production reaction from water in electrochemical or photocatalytic settings. First, produce suitable electrodes by Pt SA deposition on Direct current (DC)-sputter deposited titania (TiO2) layers on graphene-these electrodes allow to characterization of the electrochemical properties of Pt single atoms and their investigation in high-resolution HAADF-STEM. For Pt SAs loaded on TiO2, electrochemical H2 evolution shows only a very small overpotential. Concurrent with the onset of H2 evolution, agglomeration of the Pt SAs to clusters or nanoparticles (NPs) occurs. Potential cycling can be used to control SA agglomeration to variable-size NPs. The electrochemical activity of the electrode is directly related to the SA surface density (up to reaching the activity level of a plain Pt sheet). In contrast, for photocatalytic H2 generation already a minimum SA density is sufficient to reach control by photogenerated charge carriers. In electrochemical and photocatalytic approaches a typical TOF of ≈100-150 H2 molecules per second per site can be reached. Overall, the work illustrates a straightforward approach for reliable electrochemical and photoelectrochemical investigations of SAs and discusses the extraction of critical electrochemical factors of Pt SAs on titania electrodes.

Hypertension phenotypes and adverse pregnancy outcome-related office and ambulatory blood pressure thresholds during pregnancy: a retrospective cohort study.

Blood pressure (BP) phenotypes, as determined by the consistency between office BP (OBP) and ambulatory BP (ABP) measurements, enhance risk assessment during pregnancy. However, diagnostic criteria for hypertension in pregnancy are based on data from non-pregnant populations regarding long-term cardiovascular risks. This study aimed to identify adverse pregnancy outcomes (APOs; including maternal/fetal outcomes)-related BP thresholds to refine risk assessment in pregnant women. We analyzed 967 high-risk pregnant women who underwent simultaneous OBP and ABP measurements at an average gestational age of 29.6 ± 8.0 weeks. All hypertension phenotypes were associated with an increased risk of maternal and fetal outcomes, except white coat hypertension, which showed no association with fetal outcomes. Using an XGBoost algorithm, the receiver operating characteristic (ROC) curve-derived daytime diastolic BP (DBP) thresholds of 81.5 mmHg for maternal and 82.5 mmHg for fetal outcomes were identified as the BP parameters most strongly linked to APOs. Incorporating these thresholds into the BP phenotype-based model improved the area under the curve for APOs and the net reclassification index for maternal and fetal outcomes. Decision curve analysis demonstrated a consistent positive net benefit after incorporating BP thresholds into the phenotype-based model for maternal and composite outcomes. In conclusion, in a Chinese pregnancy cohort, we identified daytime DBP as the most influential parameter for APOs, significantly enhancing the predictive performance of BP phenotype-based models. This study underscores the importance of ABP monitoring in high-risk pregnancies and the need for further research to establish optimal BP monitoring criteria for pregnancy.

HOXC10 promotes hypertrophic scar fibroblast fibrosis through the regulation of STMN2 and the TGF-ß/Smad signaling pathway.

The pathophysiology of hypertrophic scar (HS) shares similarities with cancer. HOXC10, a gene significantly involved in cancer development, exhibits higher expression levels in HS than in normal skin (NS), suggesting its potential role in HS regulation. And the precise functions and mechanisms by which HOXC10 influences HS require further clarification. Gene and protein expressions were analyzed using raeal-time quantitative polymerase chain reaction (RT-qPCR) and western blot techniques. Cell proliferation and migration were evaluated using EdU proliferation assays, CCK-8 assays, scratch assays, and Transwell assays. Chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays were conducted to investigate the interactions between HOXC10 and STMN2. HOXC10 and STMN2 expression levels were significantly higher in HS tissues compared with NS tissues. Silencing HOXC10 led to decreased activation, proliferation, migration, and fibrosis in hypertrophic scar fibroblasts (HSFs). Our findings also indicate that HOXC10 directly targets STMN2. The promotional effects of HOXC10 knockdown on HSF activation, proliferation, migration, and fibrosis were reversed by STMN2 overexpression. We further demonstrated that HOXC10 regulates HSF activity through the TGF-ß/Smad signaling pathway. HOXC10 induces the activation and fibrosis of HSFs by promoting the transcriptional activation of STMN2 and engaging the TGF-ß/Smad signaling pathway. This study suggests that HOXC10 could be a promising target for developing treatments for HS.

Effect of the presence of berberine/curcumin on the binding of limonin to human serum albumin and antitumor activity in vitro.

The competition among drugs for binding to plasma proteins is regarded as a pharmacokinetic drug interaction. Competition between antitumor agents and other drugs for plasma protein binding can alter the free concentration of the drug, potentially impacting its efficacy and increasing the risk of toxic side effects. Through a range of spectroscopic techniques, this study examined the interaction between limonin and human serum albumin (HSA) in the context of berberine (Ber) and curcumin (Cur) under physiological conditions to clarify the binding mechanisms of binary and ternary systems at the molecular level. As demonstrated by fluorescence quenching experiments, Static quenching was identified as the mechanism of interaction between HSA and limonin. The results of site competition experiments indicated that the binding site between limonin and HSA was site I, a result further supported by molecular docking simulations. Through the use of thermodynamic data calculations, it was determined that limonin forms a stable complex with HSA by establishing hydrogen bonds and van der Waals forces. Circular dichroism (CD) spectroscopy, three-dimensional (3D) fluorescence spectroscopy, and synchronous fluorescence spectroscopy (SFS) employed to validate the notion that limonin perturbed the microenvironment of amino acids and induced conformational changes in HSA. What's more, the presence of Ber or Cur was found to have further modified the alterations observed in the interaction between the original HSA-limonin binary system. In vitro cellular experiments showed that interaction with HSA reduced the antitumor activity of limonin. In contrast, adding Ber or Cur increased the inhibition rate of tumor cells. The coexistence of both Ber and Cur significantly diminished limonin's binding affinity to HSA. The current investigation enhances comprehension regarding the binding characteristics and interaction mechanisms involving limonin, Ber, Cur, and HSA. It explores the potential of HSA as a versatile drug carrier and furnishes theoretical underpinnings for co-administrative strategies.

Fungal primary and opportunistic pathogens: an ecological perspective.

Fungal primary pathogenicity on vertebrates is here described as a deliberate strategy where the host plays a role in increasing the species fitness. Opportunism is defined as coincidental survival of an individual strain in host tissue using properties that are designed for life in an entirely different habitat. In that case the host's infection control is largely based on innate immunity, and the etiologic agent is not transmitted after infection, and thus fungal evolution is not possible. Primary pathogens encompass two types, depending on their mode of transmission. Environmental pathogens have a double life cycle, and tend to become enzootic, adapted to a preferred host in a particular habitat. In contrast, pathogens that have a host-to-host transmission pattern are prone to shift to a neighboring, immunologically naive host, potentially leading to epidemics. Beyond these prototypical life cycles, some environmental fungi are able to make large leaps between dissimilar hosts/habitats, probably due to similarity of key factors enabling survival in an entirely different niche, and thus allowing a change from opportunistic to primary pathogenicity. Mostly, such factors seem to be associated with extremotolerance.

Capsaicin exerts synergistic pro-apoptotic effects with cisplatin in TSCC through the calpain pathway via TRPV1.

Capsaicin (CAP) exerts significant anti-tumor effects on a variety of tumors, with low intrinsic toxicity. Cisplatin (DDP) is currently the first-line drug for the treatment of oral cancer; however, its clinical efficacy is impeded by chemoresistance and negligible side effects. Whether the combined use of CAP and DDP has a synergistic antitumor effect on tongue squamous cell carcinoma (TSCC) cells and its underlying mechanisms remains unclear. The present study revealed that CAP reduced the activity of TSCC cells in a dose- and time-dependent manner. We also observed changes in the mitochondrial functional structure of TSCC cells, along with the induction of mitochondrial apoptosis. Moreover, when CAP was combined with DDP, a synergistic cytotoxic effect on TSCC cells was observed, which had a significant impact on inducing apoptosis, inhibiting proliferation, and disrupting the mitochondrial membrane potential in TSCC cells compared to the single-drug treatment and control groups. These effects are associated with TRPV1, a high-affinity CAP receptor. The combined use of CAP and DDP can activate the TRPV1 receptor, resulting in intracellular Ca2+ overload and activation of the calpain pathway, ultimately leading to mitochondrial apoptosis. This potential mechanism was validated in TSCC xenograft models. In conclusion, our findings clearly demonstrate that CAP exerts synergistic pro-apoptotic effects with DDP in TSCC through the calpain pathway mediated by TRPV1. Thus, CAP can be considered an effective adjuvant drug for DDP in the treatment of TSCC.