Free-electron lasing at 27 nanometres based on a laser wakefield accelerator.

X-ray free-electron lasers can generate intense and coherent radiation at wavelengths down to the sub-ångström region1-5, and have become indispensable tools for applications in structural biology and chemistry, among other disciplines6. Several X-ray free-electron laser facilities are in operation2-5; however, their requirement for large, high-cost, state-of-the-art radio-frequency accelerators has led to great interest in the development of compact and economical accelerators. Laser wakefield accelerators can sustain accelerating gradients more than three orders of magnitude higher than those of radio-frequency accelerators7-10, and are regarded as an attractive option for driving compact X-ray free-electron lasers11. However, the realization of such devices remains a challenge owing to the relatively poor quality of electron beams that are based on a laser wakefield accelerator. Here we present an experimental demonstration of undulator radiation amplification in the exponential-gain regime by using electron beams based on a laser wakefield accelerator. The amplified undulator radiation, which is typically centred at 27 nanometres and has a maximum photon number of around 1010 per shot, yields a maximum radiation energy of about 150 nanojoules. In the third of three undulators in the device, the maximum gain of the radiation power is approximately 100-fold, confirming a successful operation in the exponential-gain regime. Our results constitute a proof-of-principle demonstration of free-electron lasing using a laser wakefield accelerator, and pave the way towards the development of compact X-ray free-electron lasers based on this technology with broad applications.

Asparagine Synthetase Marks a Distinct Dependency Threshold for Cardiomyocyte Dedifferentiation.

BACKGROUND: Adult mammalian cardiomyocytes have limited proliferative capacity, but in specifically induced contexts they traverse through cell-cycle reentry, offering the potential for heart regeneration. Endogenous cardiomyocyte proliferation is preceded by cardiomyocyte dedifferentiation (CMDD), wherein adult cardiomyocytes revert to a less matured state that is distinct from the classical myocardial fetal stress gene response associated with heart failure. However, very little is known about CMDD as a defined cardiomyocyte cell state in transition. METHODS: Here, we leveraged 2 models of in vitro cultured adult mouse cardiomyocytes and in vivo adeno-associated virus serotype 9 cardiomyocyte-targeted delivery of reprogramming factors (Oct4, Sox2, Klf4, and Myc) in adult mice to study CMDD. We profiled their transcriptomes using RNA sequencing, in combination with multiple published data sets, with the aim of identifying a common denominator for tracking CMDD. RESULTS: RNA sequencing and integrated analysis identified Asparagine Synthetase (Asns) as a unique molecular marker gene well correlated with CMDD, required for increased asparagine and also for distinct fluxes in other amino acids. Although Asns overexpression in Oct4, Sox2, Klf4, and Myc cardiomyocytes augmented hallmarks of CMDD, Asns deficiency led to defective regeneration in the neonatal mouse myocardial infarction model, increased cell death of cultured adult cardiomyocytes, and reduced cell cycle in Oct4, Sox2, Klf4, and Myc cardiomyocytes, at least in part through disrupting the mammalian target of rapamycin complex 1 pathway. CONCLUSIONS: We discovered a novel gene Asns as both a molecular marker and an essential mediator, marking a distinct threshold that appears in common for at least 4 models of CMDD, and revealing an Asns/mammalian target of rapamycin complex 1 axis dependency for dedifferentiating cardiomyocytes. Further study will be needed to extrapolate and assess its relevance to other cell state transitions as well as in heart regeneration.

Naringenin ameliorates MASH fibrosis via regulating TAK1/MAPK/FoxO3a-mediated apoptosis in the activated hepatic stellate cells.

This study aims to explore the regulating effect and mechanism of naringenin (NGN) on the hepatic stellate cells (HSCs) apoptosis and its preventive effects on MASH fibrosis. C57BL/6 mice were subjected to either high-fat diet (HFD) plus carbon tetrachloride (CCl4) injection (HFD + CCl4) for 8 weeks to induce a MASH fibrosis model or bile duct ligation (BDL) to establish a liver fibrosis model, NGN was administered by gavage. LX2 cells were stimulated by oleic acid (OA) and lipopolysaccharide (LPS) (OA + LPS) to study the effects of NGN on activated hepatic stellate cell (HSC). Additionally, LO2 cells stimulated with OA + LPS were used to assess the protective effects of NGN on lipotoxicity of hepatocytes. Our in vivo results showed that NGN administration effectively inhibited mouse liver fibrosis in both of the MASH model and BDL model. The in vitro results indicate that NGN directly inhibited HSCs activation and promoted apoptosis of the activated HSCs, while it suppressed the apoptosis of LO2 cells induced by OA + LPS. The underlying mechanisms were mainly elucidated through the reduction of TAK1 phosphorylation, leading to the downregulation of p-JNK and p-ERK expression. This in turn, inhibited the phosphorylation of FoxO3a and promoted the nuclear localization of FoxO3a. Consequently, this may enhance the transcription of apoptosis-related genes, resulting in the apoptosis of activated HSCs. In conclusion, NGN ameliorates MASH fibrosis by enhancing apoptosis of the activated HSCs. The inhibitory effects of NGN on the TAK1/MAPK/FoxO3a pathway were demonstrated as its preventive mechanisms against MASH fibrosis.

Gigahertz electromagnetic pulse emission from femtosecond relativistic laser-irradiated solid targets.

The interactions between high-intensity laser and matter produce particle flux and electromagnetic radiation over a wide energy range. The generation of extremely intense transient fields in the radio frequency-microwave regime has been observed in femtosecond-to-nanosecond laser pulses with 1011-1020-W/cm2 intensity on both conductive and dielectric targets. These fields typically cause saturation and damage to electronic equipment inside and near an experimental chamber; nevertheless, they can also be effectively used as diagnostic tools. Accordingly, the characterization of electromagnetic pulses (EMPs) is extremely important and currently a popular topic for present and future laser facilities intended for laser-matter interaction. The picosecond and sub-picosecond laser pulses are considerably shorter than the characteristic electron discharge time (∼0.1 ns) and can be efficient in generating GHz EMPs. The EMP characterization study of femtosecond laser-driven solid targets is currently mainly in the order of 100 mJ laser energy, in this study, the EMP generated by intense (Joule class) femtosecond laser irradiation of solid targets has been measured as a function of laser energy, laser pulse duration, focal spot size, and target materials. And a maximum electric field of the EMP reaching up to 105 V/m was measured. Analyses of experimental results confirm a direct correlation between measured EMP energy and laser parameters in the ultrashort pulse duration regime. The EMP signals generated by femtosecond laser irradiation of solid targets mainly originate from the return current inside the target after hot electron excitation. Numerical simulations of EMP are performed according to the target charging model, which agree well with the experimental results.

Pyroptosis of Vascular Smooth Muscle Cells as a Potential New Target for Preventing Vascular Diseases.

Vascular remodeling is the adaptive response of the vessel wall to physiological and pathophysiological changes, closely linked to vascular diseases. Vascular smooth muscle cells (VSMCs) play a crucial role in this process. Pyroptosis, a form of programmed cell death characterized by excessive release of inflammatory factors, can cause phenotypic transformation of VSMCs, leading to their proliferation, migration, and calcification-all of which accelerate vascular remodeling. Inhibition of VSMC pyroptosis can delay this process. This review summarizes the impact of pyroptosis on VSMCs and the pathogenic role of VSMC pyroptosis in vascular remodeling. We also discuss inhibitors of key proteins in pyroptosis pathways and their effects on VSMC pyroptosis. These findings enhance our understanding of the pathogenesis of vascular remodeling and provide a foundation for the development of novel medications that target the control of VSMC pyroptosis as a potential treatment strategy for vascular diseases.

GQ262 Attenuates Pathological Cardiac Remodeling by Downregulating the Akt/mTOR Signaling Pathway.

Cardiac remodeling, a critical process that can lead to heart failure, is primarily characterized by cardiac hypertrophy. Studies have shown that transgenic mice with Gαq receptor blockade exhibit reduced hypertrophy under induced pressure overload. GQ262, a novel Gαq/11 inhibitor, has demonstrated good biocompatibility and specific inhibitory effects on Gαq/11 compared to other inhibitors. However, its role in cardiac remodeling remains unclear. This study aims to explore the anti-cardiac remodeling effects and mechanisms of GQ262 both in vitro and in vivo, providing data and theoretical support for its potential use in treating cardiac remodeling diseases. Cardiac hypertrophy was induced in mice via transverse aortic constriction (TAC) for 4 weeks and in H9C2 cells through phenylephrine (PE) induction, confirmed with WGA and H&E staining. We found that GQ262 improved cardiac function, inhibited the protein and mRNA expression of hypertrophy markers, and reduced the levels of apoptosis and fibrosis. Furthermore, GQ262 inhibited the Akt/mTOR signaling pathway activation induced by TAC or PE, with its therapeutic effects disappearing upon the addition of the Akt inhibitor ARQ092. These findings reveal that GQ262 inhibits cardiomyocyte hypertrophy and apoptosis through the Akt/mTOR signaling pathway, thereby reducing fibrosis levels and mitigating cardiac remodeling.

Multicomponent Intervention on Improving the Cognitive Ability of Older Adults with Mild Cognitive Impairment: A Pilot Randomized Controlled Trial.

This pilot randomized controlled trial aimed to evaluate the feasibility and potential outcomes of an innovative 16-session multicomponent intervention model to improve cognitive abilities in older adults with mild cognitive impairment (MCI) by promoting healthy lifestyle, cognitive skills, tai chi and mindfulness practices. This study was a multicentre, randomized controlled, two-arm, parallel-group, unblinded trial in Hong Kong. 57 Chinese older adults with MCI recruited from three local elderly centers were randomly assigned to either the control or intervention group. The study results support the feasibility and efficacy of the multicomponent intervention, and recommend future larger-scale randomized control trials.

Comparison between gradients and parcellations for functional connectivity prediction of behavior.

Resting-state functional connectivity (RSFC) is widely used to predict behavioral measures. To predict behavioral measures, representing RSFC with parcellations and gradients are the two most popular approaches. Here, we compare parcellation and gradient approaches for RSFC-based prediction of a broad range of behavioral measures in the Human Connectome Project (HCP) and Adolescent Brain Cognitive Development (ABCD) datasets. Among the parcellation approaches, we consider group-average "hard" parcellations (Schaefer et al., 2018), individual-specific "hard" parcellations (Kong et al., 2021a), and an individual-specific "soft" parcellation (spatial independent component analysis with dual regression; Beckmann et al., 2009). For gradient approaches, we consider the well-known principal gradients (Margulies et al., 2016) and the local gradient approach that detects local RSFC changes (Laumann et al., 2015). Across two regression algorithms, individual-specific hard-parcellation performs the best in the HCP dataset, while the principal gradients, spatial independent component analysis and group-average "hard" parcellations exhibit similar performance. On the other hand, principal gradients and all parcellation approaches perform similarly in the ABCD dataset. Across both datasets, local gradients perform the worst. Finally, we find that the principal gradient approach requires at least 40 to 60 gradients to perform as well as parcellation approaches. While most principal gradient studies utilize a single gradient, our results suggest that incorporating higher order gradients can provide significant behaviorally relevant information. Future work will consider the inclusion of additional parcellation and gradient approaches for comparison.

Relationship between prediction accuracy and feature importance reliability: An empirical and theoretical study.

There is significant interest in using neuroimaging data to predict behavior. The predictive models are often interpreted by the computation of feature importance, which quantifies the predictive relevance of an imaging feature. Tian and Zalesky (2021) suggest that feature importance estimates exhibit low split-half reliability, as well as a trade-off between prediction accuracy and feature importance reliability across parcellation resolutions. However, it is unclear whether the trade-off between prediction accuracy and feature importance reliability is universal. Here, we demonstrate that, with a sufficient sample size, feature importance (operationalized as Haufe-transformed weights) can achieve fair to excellent split-half reliability. With a sample size of 2600 participants, Haufe-transformed weights achieve average intra-class correlation coefficients of 0.75, 0.57 and 0.53 for cognitive, personality and mental health measures respectively. Haufe-transformed weights are much more reliable than original regression weights and univariate FC-behavior correlations. Original regression weights are not reliable even with 2600 participants. Intriguingly, feature importance reliability is strongly positively correlated with prediction accuracy across phenotypes. Within a particular behavioral domain, there is no clear relationship between prediction performance and feature importance reliability across regression models. Furthermore, we show mathematically that feature importance reliability is necessary, but not sufficient, for low feature importance error. In the case of linear models, lower feature importance error is mathematically related to lower prediction error. Therefore, higher feature importance reliability might yield lower feature importance error and higher prediction accuracy. Finally, we discuss how our theoretical results relate with the reliability of imaging features and behavioral measures. Overall, the current study provides empirical and theoretical insights into the relationship between prediction accuracy and feature importance reliability.

Engineered Fenofibrate as Oxidation-Sensitive Nanoparticles with ROS Scavenging and PPARα-Activating Bioactivity to Ameliorate Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in western countries and China. Fenofibrate (FNB) can activate peroxisome proliferator-activated receptor α (PPARα) to increase fatty acid oxidation and ameliorate NAFLD. However, the application of FNB is limited in clinic due to its poor water solubility and low oral bioavailability. In this study, FNB-loaded nanoparticles (FNB-NP) based on a reactive oxygen species (ROS)-responsive peroxalate ester derived from vitamin E (OVE) and an amphiphilic conjugate 1,2-distearoyl-sn-glycerol-3-phosphoethanolamine-N-[methoxy(poly(ethylene glycol))-2000] (DSPE-PEG) were developed to enhance the preventive effects of FNB against NAFLD. In in vitro studies, FNB-NP displayed a high encapsulation efficiency of 97.25 ± 0.6% and a drug loading efficiency of 29.67 ± 0.1%, with a size of 197.0 ± 0.2 nm. FNB released from FNB-NP was dramatically accelerated in the medium with high H2O2 concentrations. Moreover, FNB-NP exhibited well storage stability and plasma stability. In pharmacokinetic (PK) studies, FNB-NP, compared with FNB crude drug, significantly increased the AUC0→t and AUC0→∞ of the plasma FNB acid by 3.3- and 3.4-fold, respectively. In pharmacodynamics (PD) studies, compared with an equal dose of FNB crude drug, FNB-NP more significantly reduced hepatic lipid deposition via facilitating FNB release in the liver and further upregulating PPARα expression in NAFLD mice. Meanwhile, oxidative stress in NAFLD was significantly suppressed after FNB-NP administration, suggesting that OVE plays a synergistic effect on antioxidation. Therefore, ROS-sensitive FNB delivery formulations FNB-NP enhance the preventive effects of FNB against NAFLD and could be further studied as a promising drug for the treatment of NAFLD in clinic.

BATF Regulates T Regulatory Cell Functional Specification and Fitness of Triglyceride Metabolism in Restraining Allergic Responses.

Preserving appropriate function and metabolism in regulatory T (Treg) cells is crucial for controlling immune tolerance and inflammatory responses. Yet how Treg cells coordinate cellular metabolic programs to support their functional specification remains elusive. In this study, we report that BATF couples the TH2-suppressive function and triglyceride (TG) metabolism in Treg cells for controlling allergic airway inflammation and IgE responses. Mice with Treg-specific ablation of BATF developed an inflammatory disorder characterized by TH2-type dominant responses and were predisposed to house dust mite-induced airway inflammation. Loss of BATF enabled Treg cells to acquire TH2 cell-like characteristics. Moreover, BATF-deficient Treg cells displayed elevated levels of cellular TGs, and repressing or elevating TGs, respectively, restored or exacerbated their defects. Mechanistically, TCR/CD28 costimulation enhanced expression and function of BATF, which sustained IRF4 activity to preserve Treg cell functionality. Thus, our studies reveal that BATF links Treg cell functional specification and fitness of cellular TGs to control allergic responses, and suggest that therapeutic targeting of TG metabolism could be used for the treatment of allergic disease.

Agathis dammara Extract and its Monomer Araucarone Attenuate Abdominal Aortic Aneurysm in Mice.

BACKGROUND: Abdominal aortic aneurysm (AAA) is a chronic vascular disease wherein the inflammation of vascular smooth muscle cells (VSMCs) plays a pivotal role in its development. Effectively mitigating AAA involves inhibiting VSMC inflammation. Agathis dammara (Lamb.) Rich, recognized for its robust anti-inflammatory and antioxidant attributes, has been employed as a traditional medicinal resource. Nonetheless, there is a dearth of information regarding the potential of Agathis dammara extract (AD) in attenuating AAA, specifically by diminishing vascular inflammation, notably VSMC inflammation. Furthermore, the active constituents of AD necessitate identification. AIM OF THE STUDY: This study sought to ascertain the efficacy of AD in reducing AAA, evaluate its impact on VSMC inflammation, and elucidate whether the monomer araucarone (AO) in AD acts as an active component against AAA. MATERIALS AND METHODS: The extraction of AD was conducted and subjected to analysis through High-Performance Liquid Chromatography (HPLC) and mass spectrometry. The isolation of the AO monomer followed, involving the determination of its content and purity. Subsequently, the effects of AD and AO on VSMC inflammation were assessed in vitro, encompassing an examination of inflammatory factors such as IL-6 and IL-18, as well as the activation of matrix metalloproteinase 9 (MMP9) in tumor necrosis factor-alpha (TNF-α)-stimulated VSMCs. To explore the inhibitory effects of AD/AO on AAA, C57BL/6J male mice were subjected to oral gavage (100 mg/kg) or intraperitoneal injection (50 mg/kg) of AD and AO in a porcine pancreatic elastase (PPE)-induced AAA model (14 days). This facilitated the observation of abdominal aorta dilatation, remodeling, elastic fiber disruption, and macrophage infiltration. Additionally, a three-day PPE mouse model was utilized to assess the effects of AD and AO (administered at 100 mg/kg via gavage) on acute inflammation and MMP9 expression in blood vessels. The mechanism by which AD/AO suppresses the inflammatory response was probed through the examination of NF-κB/NLRP3 pathway activation in VSMCs and aortas. RESULTS: Liquid Chromatography-Mass Spectrometry (LC-MS) revealed that AO constituted 15.36% of AD's content, with a purity of 96%. Subsequent pharmacological investigations of AO were conducted in parallel with AD. Both AD and AO exhibited the ability to inhibit TNF-α-induced VSMC inflammation and MMP production in vitro. Furthermore, both substances effectively prevented PPE-induced AAA in mice, whether administered through gavage or intraperitoneal injection, evidenced by decreased vascular diameter dilation, disruption of elastin fiber layers, and infiltration of inflammatory cells. In the three-day PPE mouse model, AD and AO mitigated the heightened expression of inflammatory factors and the elevated expression of MMP9 induced by PPE. The activation of the NF-κB/NLRP3 pathway in both VSMCs and aortas was significantly suppressed by treatment with AD or AO. CONCLUSIONS: Through suppressing NF-κB/NLRP3 pathway activation, AD effectively mitigates the inflammatory response in VSMCs, mitigates inflammation in aortas, prevents extracellular matrix degradation, and consequently impedes the progression of AAA. AO emerges as one of the active compounds in AD responsible for inhibiting VSMC inflammation and inhibiting AAA development.

HIV associated factors among men who have sex with men in Maanshan, China: a cross-sectional study.

BACKGROUND: This study conducted a survey of men who have sex with men (MSM) in Maanshan City of Anhui Province to assess the risk behaviors related to human immunodeficiency virus (HIV) infection. METHODS: A cross-sectional survey was conducted from June 2016 to June 2019. The MSM were recruited by a peer-driven sampling method. A face-to-face interview with anonymous questionnaire was used for data collection. The information collected by the survey was summarized and epidemiology described the basic characteristics of MSM, and then the related factors were statistically analyzed. RESULTS: A total of 934 MSM were recruited with a average age was 30.5 (SD = 8.90) years old, including 816 (87.4%) HIV negative participants and 118 (12.6%) HIV positive ones. This study showed that freelancer (OR = 4.02, 95% CI: 1.96-8.23), scope of sexual partners distribution (OR = 1.78, 95% CI: 1.36-2.33), number of male sexual partners (OR = 2.11, 95% CI: 1.47-3.02), role of anal sex with men was receptive (OR = 2.54, 95% CI: 1.25-5.13) and versatile (OR = 2.34, 95% CI: 1.31-4.19) and non-steady sex partners (OR = 2.14, 95% CI: 1.56-2.93) were risk factors for HIV infection, while monthly income (OR = 0.68, 95% CI: 0.57-0.82), education level (OR = 0.79, 95% CI: 0.66-0.95), frequency of condom use (OR = 0.53, 95% CI: 0.35-0.81) and number of oral sex partners (OR = 0.35, 95% CI: 0.24-0.51) in the past 6 months were protective factors for HIV infection. CONCLUSION: Risk behaviors were common in MSM, and urgent need for targeted and comprehensive interventions to reduce risky sexual behaviour and to prevent HIV infection in MSM.

Proportional intracranial volume correction differentially biases behavioral predictions across neuroanatomical features, sexes, and development.

Individual differences in brain anatomy can be used to predict variations in cognitive ability. Most studies to date have focused on broad population-level trends, but the extent to which the observed predictive features are shared across sexes and age groups remains to be established. While it is standard practice to account for intracranial volume (ICV) using proportion correction in both regional and whole-brain morphometric analyses, in the context of brain-behavior predictions the possible differential impact of ICV correction on anatomical features and subgroups within the population has yet to be systematically investigated. In this work, we evaluate the effect of proportional ICV correction on sex-independent and sex-specific predictive models of individual cognitive abilities across multiple anatomical properties (surface area, gray matter volume, and cortical thickness) in healthy young adults (Human Connectome Project; n = 1013, 548 females) and typically developing children (Adolescent Brain Cognitive Development study; n = 1823, 979 females). We demonstrate that ICV correction generally reduces predictive accuracies derived from surface area and gray matter volume, while increasing predictive accuracies based on cortical thickness in both adults and children. Furthermore, the extent to which predictive models generalize across sexes and age groups depends on ICV correction: models based on surface area and gray matter volume are more generalizable without ICV correction, while models based on cortical thickness are more generalizable with ICV correction. Finally, the observed neuroanatomical features predictive of cognitive abilities are unique across age groups regardless of ICV correction, but whether they are shared or unique across sexes (within age groups) depends on ICV correction. These findings highlight the importance of considering individual differences in ICV, and show that proportional ICV correction does not remove the effects of cranial volume from anatomical measurements and can introduce ICV bias where previously there was none. ICV correction choices affect not just the strength of the relationships captured, but also the conclusions drawn regarding the neuroanatomical features that underlie those relationships.

Comparison of individualized behavioral predictions across anatomical, diffusion and functional connectivity MRI.

A fundamental goal across the neurosciences is the characterization of relationships linking brain anatomy, functioning, and behavior. Although various MRI modalities have been developed to probe these relationships, direct comparisons of their ability to predict behavior have been lacking. Here, we compared the ability of anatomical T1, diffusion and functional MRI (fMRI) to predict behavior at an individual level. Cortical thickness, area and volume were extracted from anatomical T1 images. Diffusion Tensor Imaging (DTI) and approximate Neurite Orientation Dispersion and Density Imaging (NODDI) models were fitted to the diffusion images. The resulting metrics were projected to the Tract-Based Spatial Statistics (TBSS) skeleton. We also ran probabilistic tractography for the diffusion images, from which we extracted the stream count, average stream length, and the average of each DTI and NODDI metric across tracts connecting each pair of brain regions. Functional connectivity (FC) was extracted from both task and resting-state fMRI. Individualized prediction of a wide range of behavioral measures were performed using kernel ridge regression, linear ridge regression and elastic net regression. Consistency of the results were investigated with the Human Connectome Project (HCP) and Adolescent Brain Cognitive Development (ABCD) datasets. In both datasets, FC-based models gave the best prediction performance, regardless of regression model or behavioral measure. This was especially true for the cognitive component. Furthermore, all modalities were able to predict cognition better than other behavioral components. Combining all modalities improved prediction of cognition, but not other behavioral components. Finally, across all behaviors, combining resting and task FC yielded prediction performance similar to combining all modalities. Overall, our study suggests that in the case of healthy children and young adults, behaviorally-relevant information in T1 and diffusion features might reflect a subset of the variance captured by FC.

All-in-One Theranostic Platform Based on Hollow Microcapsules for Intragastric-Targeting Antiulcer Drug Delivery, CT Imaging, and Synergistically Healing Gastric Ulcer.

Bismuth-containing therapies are suggested as first-line and rescue alternatives for gastric ulcer (GU) treatment and Helicobacter pylori eradication. The current treatment strategy is called quadruple therapy and includes proton pump inhibitors, bismuth, and two broad-band antibiotics. This fact may affect medication compliance, leading to a resistance rate of more than 25% to clarithromycin or metronidazole. To counter this, from the perspective of natural products, an intragastric-targeting all-in-one theranostic platform is established: a drug carrier microcapsule composed of multiple synergistic antiulcer drugs, including bismuth, gallotannin, and antibiotics is obtained (BiG@MCs), and the therapeutic effects of BiG@MCs in rodent models are further evaluated. The results show that the BiG@MCs are spherical with homogeneous particle size (3 ± 0.5 µm) and can be response-released to the acidic environment of the stomach (pH 2.0-3.0), preventing the premature release of the BiG@MCs in physiological conditions. It is worth noting that the bismuth component can be easily identified by computed tomography and other detection instruments, which provide the possibility for drug tracing. In summary, these results indicate that BiG@MCs provide a versatile intragastric-targeting drug delivery platform for GU therapeutics.

Measurement of myocardial extracellular volume fraction in patients with heart failure with preserved ejection fraction using dual-energy computed tomography.

OBJECTIVES: To measure the myocardial extracellular volume (ECV) in patients with heart failure with preserved ejection fraction (HFpEF) using dual-energy computed tomography with late iodine enhancement (LIE-DECT) and to evaluate the relationship between ECV and risk of HFpEF and cardiac structure and function. METHODS: A total of 112 consecutive patients with HFpEF and 80 consecutive subjects without heart disease (control group) who underwent LIE-DECT were included. All patients were divided into ischaemic and non-ischaemic groups according to the LIE patterns detected using iodine maps. The ischaemic scar burden was calculated in the ischaemic HFpEF group. Iodine maps and haematocrit were used to measure ECV in the non-ischaemic HFpEF group and remote ECV of the non-scarred myocardium in the ischaemic HFpEF group, respectively. Cardiac structural and functional variables were collected. RESULTS: ECV in patients with non-ischaemic HFpEF (n = 77) and remote ECV in patients with ischaemic HFpEF (n = 35) were significantly higher than those in control subjects (p < 0.001). Multivariate logistic regression analysis revealed that after adjusting for age, sex, body mass index, smoking, and drinking, a higher ECV/remote ECV was still associated with non-ischaemic HFpEF and ischaemic HFpEF (p < 0.001). A positive correlation was established between ECV and cardiac structural and functional variables (p < 0.05) in all participants. Subgroup analysis showed that ECV/remote ECV and ischaemic scar burden positively correlated with heart failure classification in the HFpEF subgroup (p < 0.05). CONCLUSION: ECV/remote ECV elevation was significantly associated with non-ischaemic and ischaemic HFpEF. Remote ECV and LIE may have synergistic effects in the risk assessment of ischaemic HFpEF. KEY POINTS: • ECV/remote ECV elevation is associated not only with non-ischaemic HFpEF but also with ischaemic HFpEF. • ECV/remote ECV and ischaemic scar burden are correlated with cardiac structure and function.

Molecular Trade-Offs between Lattice Oxygen and Oxygen Vacancy Drive Organic Pollutant Degradation in Fungal Biomineralized Exoskeletons.

Fungal-mineral interactions can effectively alleviate cellular stress from organic pollutants, the production of which are expected to rapidly increase owing to the Earth moving into an unprecedented geological epoch, the Anthropocene. The underlying mechanisms that may enable fungi to combat organic pollution during fungal-mineral interactions remain unclear. Inspired by the natural fungal sporulation process, we demonstrate for the first time that fungal biomineralization triggers the formation of an ultrathin (hundreds of nanometers thick) exoskeleton, enriched in nanosized iron (oxyhydr)oxides and biomolecules, on the hyphae. Mapped biochemical composition of this coating at a subcellular scale via high spatial resolution (down to 50 nm) synchrotron radiation-based techniques confirmed aromatic C, C-N bonds, amide carbonyl, and iron (oxyhydr)oxides as the major components of the coatings. This nanobiohybrid system appeared to impart a strong (×2) biofunctionality for fungal degradation of bisphenol A through altering molecular-level trade-offs between lattice oxygen and oxygen vacancy. Together, fungal coatings could act as "artificial spores", which enable fungi to combat physical and chemical stresses in natural environments, providing crucial insights into fungal biomineralization and coevolution of the Earth's lithosphere and biosphere.

HPMC improves protective effects of naringenin and isonicotinamide co-crystals against abdominal aortic aneurysm.

PURPOSE: Abdominal aortic aneurysm (AAA) rupture is one of the most common causes of mortality in cardiovascular diseases, but currently there is no approved drug for AAA treatment or prevention in the clinic. Naringenin (NGN) has been reported to have anti-AAA effects. However, water solubility and in vivo absorption of NGN are not satisfactory, which leads to its low bioavailability, thus affecting its pharmacological effects. In this project, the improving effects of isonicotinamide (INT) co-crystal and hydroxy propyl methyl cellulose (HPMC) or polyvinyl pyrrolidone (PVP) on the solubility, in vivo absorption, and anti-AAA effects of NGN were evaluated. METHODS: In the current study, co-crystals of naringenin-isonicotinamide (NGN-INT) were prepared, and effects of PVP or HPMC on precipitation rate, supersaturation, and bioavailability of NGN were explored. In addition, with or without HPMC supply, the effects of NGN-INT co-crystal on anti-AAA efficacy of NGN were investigated on an elastase-induced AAA mouse model, and the results were compared with the efficacy of the NGN crude drug. RESULTS: Our results demonstrate that NGN-INT formulation, compared to the NGN crude drug, enhanced the dissolution rate of NGN and significantly increased Cmax and AUC(0-∞) of NGN by 18 times and 1.97 times, respectively. Addition of PVP or HPMC in NGN-INT co-crystal further increased bioavailability of NGN in NGN-INT. The in vivo pharmacodynamic study showed that NGN-INT with HPMC significantly improved the inhibitory effects of NGN against AAA. CONCLUSION: NGN-INT significantly improved the absorption and aortic protective effects of NGN. The supersaturation-prolonging effect of HPMC further enhanced bioavailability and anti-AAA effects of NGN-INT.

Predicting pharmacotherapeutic outcomes for type 2 diabetes: An evaluation of three approaches to leveraging electronic health record data from multiple sources.

Electronic health record (EHR) data are increasingly used to develop prediction models to support clinical care, including the care of patients with common chronic conditions. A key challenge for individual healthcare systems in developing such models is that they may not be able to achieve the desired degree of robustness using only their own data. A potential solution-combining data from multiple sources-faces barriers such as the need for data normalization and concerns about sharing patient information across institutions. To address these challenges, we evaluated three alternative approaches to using EHR data from multiple healthcare systems in predicting the outcome of pharmacotherapy for type 2 diabetes mellitus(T2DM). Two of the three approaches, named Selecting Better (SB) and Weighted Average(WA), allowed the data to remain within institutional boundaries by using pre-built prediction models; the third, named Combining Data (CD), aggregated raw patient data into a single dataset. The prediction performance and prediction coverage of the resulting models were compared to single-institution models to help judge the relative value of adding external data and to determine the best method to generate optimal models for clinical decision support. The results showed that models using WA and CD achieved higher prediction performance than single-institution models for common treatment patterns. CD outperformed the other two approaches in prediction coverage, which we defined as the number of treatment patterns predicted with an Area Under Curve of 0.70 or more. We concluded that 1) WA is an effective option for improving prediction performance for common treatment patterns when data cannot be shared across institutional boundaries and 2) CD is the most effective approach when such sharing is possible, especially for increasing the range of treatment patterns that can be predicted to support clinical decision making.