A Computational Model of the Electrically or Acoustically Evoked Compound Action Potential in Cochlear Implant Users with Residual Hearing.

OBJECTIVE: In cochlear implant users with residual acoustic hearing, compound action potentials (CAPs) can be evoked by acoustic (aCAP) or electric (eCAP) stimulation and recorded through the electrodes of the implant. We propose a novel computational model to simulate aCAPs and eCAPs in humans, considering the interaction between combined electric-acoustic stimulation that occurs in the auditory nerve. METHODS: The model consists of three components: a 3D finite element method model of an implanted cochlea, a phenomenological single-neuron spiking model for electric-acoustic stimulation, and a physiological multi-compartment neuron model to simulate the individual nerve fiber contributions to the CAP. RESULTS: The CAP morphologies closely resembled those known from humans. The spread of excitation derived from eCAPs by varying the recording electrode along the cochlear implant electrode array was consistent with published human data. The predicted CAP amplitude growth functions largely resembled human data, with deviations in absolute CAP amplitudes for acoustic stimulation. The model reproduced the suppression of eCAPs by simultaneously presented acoustic tone bursts for different masker frequencies and probe stimulation electrodes. CONCLUSION: The proposed model can simulate CAP responses to electric, acoustic, or combined electric-acoustic stimulation. It considers the dependence on stimulation and recording sites in the cochlea, as well as the interaction between electric and acoustic stimulation in the auditory nerve. SIGNIFICANCE: The model enhances comprehension of CAPs and peripheral electric-acoustic interaction. It can be used in the future to investigate objective methods, such as hearing threshold assessment or estimation of neural health through aCAPs or eCAPs.

Spermbots and Their Applications in Assisted Reproduction: Current Progress and Future Perspectives.

Sperm quality is declining dramatically during the past decades. Male infertility has been a serious health and social problem. The sperm cell driven biohybrid nanorobot opens a new era for automated and precise assisted reproduction. Therefore, it is urgent and necessary to conduct an updated review and perspective from the viewpoints of the researchers and clinicians in the field of reproductive medicine. In the present review, we first update the current classification, design, control and applications of various spermbots. Then, by a comprehensive summary of the functional features of sperm cells, the journey of sperms to the oocyte, and sperm-related dysfunctions, we provide a systematic guidance to further improve the design of spermbots. Focusing on the translation of spermbots into clinical practice, we point out that the main challenges are biocompatibility, effectiveness, and ethical issues. Considering the special requirements of assisted reproduction, we also propose the three laws for the clinical usage of spermbots: good genetics, gentle operation and no contamination. Finally, a three-step roadmap is proposed to achieve the goal of clinical translation. We believe that spermbot-based treatments can be validated and approved for in vitro clinical usage in the near future. However, multi-center and multi-disciplinary collaborations are needed to further promote the translation of spermbots into in vivo clinical applications.

Association between dietary supplement use and mortality in cancer survivors with different body mass index and frailty status: a cohort study.

Background: The association between Body Mass Index (BMI), frailty index (FI), and dietary supplement in cancer survivors has been a subject of growing interest. This study investigates the relationship of BMI and FI with mortality in American cancer survivors and explores the impact of dietary supplement usage on different BMI and FI groups. Methods: Three thousand nine hundred and thirty-two cancer patients from the National Health and Nutrition Examination Survey (NHANES) database were included in the analyses. BMI, FI, and supplement usage were obtained through the NHANES structured survey and the 49-item FI tool. Weighted logistic and Cox proportional hazards models, Kaplan-Meier survival analyses, and propensity score matching (PSM) were used to elucidate the relationships between BMI, FI, dietary supplement, and mortality outcomes. Results: The study found significant associations between higher BMI and increased frailty (Odds ratio [OR] = 1.04, 95% confidence interval [95% CI], 1.02-1.06). BMI < 25 kg/m2 and FI > 0.2 are associated with an increased mortality rate. Dietary supplement use can reduce all-cause and cancer mortality in cancer patients with BMI < 25 kg/m2 (Hazard ratio [HR] = 0.63, 95% CI, 0.47-0.84; HR = 0.48, 95% CI, 0.29-0.80) or FI ≤ 0.2 (HR = 0.77, 95% CI, 0.60-0.99; HR = 0.59, 95% CI, 0.39-0.89). In cancer patients with BMI < 25 kg/m2 and FI ≤ 0.2, dietary supplement users had lower all-cause and cancer mortality (HR = 0.49, 95% CI, 0.30-0.79; HR = 0.25, 95% CI, 0.10-0.60). Conclusion: The study revealed a negative correlation between BMI and the FI among the cancer patient cohort as well as their complex impact on mortality and highlighted the role of dietary supplement in cancer prognosis, indicating benefits for non-frail patients with BMI < 25 kg/m2.

High-throughput enrichment of portal venous circulating tumor cells for highly sensitive diagnosis of CA19-9-negative pancreatic cancer patients using inertial microfluidics.

The carbohydrate antigen 19-9 (CA19-9) is commonly used as a representative biomarker for pancreatic cancer (PC); however, it lacks sensitivity and specificity for early-stage PC diagnosis. Furthermore, some patients with PC are negative for CA19-9 (<37 U/mL), which introduces additional limitations to their accurate diagnosis and treatment. Hence, improved methods to accurately detect PC stages in CA19-9-negative patients are warranted. In this study, tumor-proximal liquid biopsy and inertial microfluidics were coupled to enable high-throughput enrichment of portal venous circulating tumor cells (CTCs) and support the effective diagnosis of patients with early-stage PC. The proposed inertial microfluidic system was shown to provide size-based enrichment of CTCs using inertial focusing and Dean flow effects in slanted spiral channels. Notably, portal venous blood samples were found to have twice the yield of CTCs (21.4 cells per 5 mL) compared with peripheral blood (10.9 CTCs per 5 mL). A combination of peripheral and portal CTC data along with CA19-9 results showed to greatly improve the average accuracy of CA19-9-negative PC patients from 47.1% with regular CA19-9 tests up to 87.1%. Hence, portal venous CTC-based microfluidic biopsy can be used with high sensitivity and specificity for the diagnosis of early-stage PC, particularly in CA19-9-negative patients.

Phosphorylated protein chip combined with artificial intelligence tools for precise drug screening.

We have developed a protein array system, named "Phospho-Totum", which reproduces the phosphorylation state of a sample on the array. The protein array contains 1471 proteins from 273 known signaling pathways. According to the activation degrees of tyrosine kinases in the sample, the corresponding groups of substrate proteins on the array are phosphorylated under the same conditions. In addition to measuring the phosphorylation levels of the 1471 substrates, we have developed and performed the artificial intelligence-assisted tools to further characterize the phosphorylation state and estimate pathway activation, tyrosine kinase activation, and a list of kinase inhibitors that produce phosphorylation states similar to that of the sample. The Phospho-Totum system, which seamlessly links and interrogates the measurements and analyses, has the potential to not only elucidate pathophysiological mechanisms in diseases by reproducing the phosphorylation state of samples, but also be useful for drug discovery, particularly for screening targeted kinases for potential drug kinase inhibitors.

Preventing thermal aggregation of ovalbumin through dielectric-barrier discharge plasma treatment and enhancing its emulsification properties.

The impact of Dielectric-Barrier Discharge (DBD) plasma treatment on the prevention of heat-induced aggregation of Ovalbumin (OVA) and improvement in emulsification properties was investigated. Results highlighted the effective inhibition of thermal aggregation of OVA following exposure to plasma. Structural analysis revealed that the plasma-induced oxidation of sulfhydryl and intermolecular disulfide bonds played a pivotal role in inhibiting the thermal aggregation, considered by Sodium Dodecyl Sulfate Polyacrylamide Gel Electrophoresis (SDS-PAGE), multiplies spectroscopy, and analysis of dynamic exchange of sulfhydryl-disulfide bonds. Meanwhile, the oxidation of exposed hydrophobic sites due to plasma treatment resulted in the transformation of the OVA molecule's surface from hydrophobic to hydrophilic, contributing significantly to the aggregation inhibition. Additionally, compared to an untreated sample of OVA, almost one-fold increase in emulsifying ability (EAI) and 1.5-fold in emulsifying stability (ESI) was observed after 4 min of plasma treatment. These findings demonstrated that plasma treatment not only enhanced the thermal stability of OVA, but also improved its emulsification properties.

Exhaled volatolomics profiling facilitates personalized screening for gastric cancer.

Gastric cancer (GC) is one of the most fatal cancers, characterized by non-specific early symptoms and difficulty in detection. However, there are no valid non-invasive screening tools available for GC. Here we establish a non-invasive method that employs exhaled volatolomics and ensemble learning to detect GC. We developed a comprehensive mass spectrometry-based procedure and determined of a wide range of volatolomics from 314 breath samples. The discovery, identification and verification research screened a biomarker panel to distinguish GC from controls. This panel has achieved 0.90 (0.87-0.94, 95%CI) accuracy, with an area under curve (AUC) of 0.92 (0.89-0.94, 95%CI) in discovery cohort and 0.88 (0.83-0.91, 95%CI) accuracy with an AUC of 0.91 (0.87-0.93, 95%CI) in replication cohort, which outperformed traditional serum markers. Single-cell sequencing and gene set enrichment analysis revealed that these exhaled markers originated from aldehyde oxidation and pyruvate metabolism. Our approach advances the design of exhaled analysis for GC detection and holds promise as a non-invasive method to the clinic.

Cell communication pathway prognostic model identified detrimental neurodevelopmental pathways in neuroblastoma.

Neurodevelopmental cell communication plays a crucial role in neuroblastoma prognosis. However, determining the impact of these communication pathways on prognosis is challenging due to limited sample sizes and patchy clinical survival information of single cell RNA-seq data. To address this, we have developed the cell communication pathway prognostic model (CCPPM) in this study. CCPPM involves the identification of communication pathways through single-cell RNA-seq data, screening of prognosis-significant pathways using bulk RNA-seq data, conducting functional and attribute analysis of these pathways, and analyzing the post-effects of communication within these pathways. By employing the CCPPM, we have identified ten communication pathways significantly influencing neuroblastoma, all related to axongenesis and neural projection development, especially the BMP7-(BMPR1B-ACVR2B) communication pathway was found to promote tumor cell migration by activating the transcription factor SMAD1 and regulating UNK and MYCBP2. Notably, BMP7 expression was higher in neuroblastoma samples with distant metastases. In summary, CCPPM offers a novel approach to studying the influence of cell communication pathways on disease prognosis and identified detrimental communication pathways related to neurodevelopment.

Targeted Delivery of Catalase and Photosensitizer Ce6 by a Tumor-Specific Aptamer Is Effective against Bladder Cancer In Vivo.

Photodynamic therapy (PDT) is often applied in a clinical setting to treat bladder cancer. However, current photosensitizers report drawbacks such as low efficacy, low selectivity, and numerous side effects, which have limited the clinical values of PDT for bladder cancer. Previously, we developed the first bladder cancer-specific aptamer that can selectively bind to and be internalized by bladder tumor cells versus normal uroepithelium cells. Here, we use an aptamer-based drug delivery system to deliver photosensitizer chlorine e6 (Ce6) into bladder tumor cells. In addition to Ce6, we also incorporate catalase into the drug complex to increase local oxygen levels in the tumor tissue. Compared with free Ce6, an aptamer-guided DNA nanotrain (NT) loaded with Ce6 and catalase (NT-Catalase-Ce6) can specifically recognize bladder cancer cells, produce oxygen locally, induce ROS in tumor cells, and cause mitochondrial apoptosis. In an orthotopic mouse model of bladder cancer, the intravesical instillation of NT-Catalase-Ce6 exhibits faster drug internalization and a longer drug retention time in tumor tissue compared with that in normal urothelium. Moreover, our modified PDT significantly inhibits tumor growth with fewer side effects such as cystitis than free Ce6. This aptamer-based photosensitizer delivery system can therefore improve the selectivity and efficacy and reduce the side effects of PDT treatment in mouse models of bladder cancer, bearing a great translational value for bladder cancer intravesical therapy.

Deficient gait function despite effect index of the Western Ontario and McMaster university osteoarthritis index score considered cured one year after bilateral total knee arthroplasty.

BACKGROUND: To clarify the value of gait analysis and its consistency with traditional scoring scales for the evaluation of knee joint function after total knee arthroplasty (TKA). METHODS: This study included 25 patients with knee osteoarthritis (KOA) who underwent bilateral TKA, and 25 conditionally matched healthy individuals, categorised into the experimental and control groups, respectively. Patients in the experimental group underwent gait analysis and Western Ontario and McMaster University Osteoarthritis Index (WOMAC) evaluation before and 1 year after TKA. Weight-bearing balance and walking stability were assessed using discrete trends of relevant gait indicators. Pearson's correlation analysis was performed on the gait and WOMAC score data of the experimental group before and after TKA. RESULTS: One year after TKA, patients' gait indices (except gait cycle) were significantly better than before surgery, but significantly worse than that of the control group (P < 0.01). The shape of patients' plantar pressure curves did not return to normal. Additionally, the discrete trend of related gait indicators reflecting weight-bearing balance and walking stability were smaller than before TKA, but still greater than that of the control group. The WOMAC scores of patients 1 year after TKA were significantly lower than those before TKA (P < 0.001), and the efficacy index was > 80%. The WOMAC scores and gait analysis results were significantly correlated before TKA (P < 0.05). CONCLUSIONS: Gait analysis should be used in conjunction with scoring scales to assess joint functions.

RNA m6A methylation and regulatory proteins in pulmonary arterial hypertension.

m6A (N6­methyladenosine) is the most common and abundant apparent modification in mRNA of eukaryotes. The modification of m6A is regulated dynamically and reversibly by methyltransferase (writer), demethylase (eraser), and binding protein (reader). It plays a significant role in various processes of mRNA metabolism, including regulation of transcription, maturation, translation, degradation, and stability. Pulmonary arterial hypertension (PAH) is a malignant cardiopulmonary vascular disease characterized by abnormal proliferation of pulmonary artery smooth muscle cells. Despite the existence of several effective and targeted therapies, there is currently no cure for PAH and the prognosis remains poor. Recent studies have highlighted the crucial role of m6A modification in cardiovascular diseases. Investigating the role of RNA m6A methylation in PAH could provide valuable insights for drug development. This review aims to explore the mechanism and function of m6A in the pathogenesis of PAH and discuss the potential targeting of RNA m6A methylation modification as a treatment for PAH.

Bioactive materials from berberine-treated human bone marrow mesenchymal stem cells promote alveolar bone regeneration by regulating macrophage polarization.

Alveolar bone regeneration has been strongly linked to macrophage polarization. M1 macrophages aggravate alveolar bone loss, whereas M2 macrophages reverse this process. Berberine (BBR), a natural alkaloid isolated and refined from Chinese medicinal plants, has shown therapeutic effects in treating metabolic disorders. In this study, we first discovered that culture supernatant (CS) collected from BBR-treated human bone marrow mesenchymal stem cells (HBMSCs) ameliorated periodontal alveolar bone loss. CS from the BBR-treated HBMSCs contained bioactive materials that suppressed the M1 polarization and induced the M2 polarization of macrophages in vivo and in vitro. To clarify the underlying mechanism, the bioactive materials were applied to different animal models. We discovered macrophage colony-stimulating factor (M-CSF), which regulates macrophage polarization and promotes bone formation, a key macromolecule in the CS. Injection of pure M-CSF attenuated experimental periodontal alveolar bone loss in rats. Colony-stimulating factor 1 receptor (CSF1R) inhibitor or anti-human M-CSF (M-CSF neutralizing antibody, Nab) abolished the therapeutic effects of the CS of BBR-treated HBMSCs. Moreover, AKT phosphorylation in macrophages was activated by the CS, and the AKT activator reversed the negative effect of the CSF1R inhibitor or Nab. These results suggest that the CS of BBR-treated HBMSCs modulates macrophage polarization via the M-CSF/AKT axis. Further studies also showed that CS of BBR-treated HBMSCs accelerated bone formation and M2 polarization in rat teeth extraction sockets. Overall, our findings established an essential role of BBR-treated HBMSCs CS and this might be the first report to show that the products of BBR-treated HBMSCs have active effects on alveolar bone regeneration.

Risk and Incidence of Cardiovascular Disease Associated with Polycystic Ovary Syndrome.

AIMS: We aimed to evaluate the risk of cardiovascular disease (CVD) in women with polycystic ovary syndrome (PCOS) and estimate the global incidence of PCOS-associated CVD. METHODS: We conducted a meta-analysis across five databases to evaluate the risk of CVD among women with PCOS. Global incidence of PCOS-associated CVD was calculated by a population attributable fraction (PAF) modelling using the pooled RR, PCOS prevalence, CVD incidence number and age-standardized rate (ASIR), from the Global Burden of Diseases 2019. An estimated annual percentage change (EAPC) was used to assess the temporal trend of PCOS-associated CVD. RESULTS: The risk of CVD was significantly increased in the women with PCOS for all-age group (pooled RR 1.51, 95% CI 1.36-1.69), and 10- to 54-year-old (1.37, 1.17-1.59). Globally, from 1990 to 2019, the PCOS associated CVD cases in women across all-age group has rised from 102 530 to 235 560. The most affected regions were East Asia & Pacific (108 430, 66 090-166 150) in 2019. The South Asia has the highest increase trend of PCOS-associated CVD ASIRs (EAPC 2.61%, 2.49-2.73). The annual increase ASIR in PCOS-CVD incidence for the 10-54 age group (EAPC 0.49%; 0.41-0.56) is faster than that of the all-age group (0.34; 0.27-0.42). The middle- or low-middle sociodemographic index countries, experienced higher increase trend of CVD due to PCOS in the past thirty years. CONCLUSIONS: Women with PCOS have a significantly increased risk of CVD. Efficient measures to enhance its prevention and treatment are important for regions with high PCOS-associated CVD burden, especially premature CVD in women under 55 years.

Studies have reported cardiovascular disease (CVD) is the leading cause of mortality for women. Meanwhile, women with polycystic ovary syndrome (PCOS) substantially elevate the risk of CVD. However, no studies have quantified the impact of PCOS on the overall CVD burden. This study performed a meta-analysis to assess the risk of CVD in all-age group and 10 to 54 years old women, living with PCOS with 17 articles, and estimated the burdens of PCOS-associated CVD burden, by global, 7 World-bank defined regions, and 204 countries, from 1990 to 2019, using a PAF modelling. Our study implicated women in all-age group, and 10 to 54 years old with PCOS face a 1.51-fold, and 1.37-fold increased risk of CVD compared those without, respectively. Globally, approximately 0.85% of CVD new cases in 2019 were associated with PCOS, corresponded a more than 2-fold increase of PCOS-associated CVD cases from 1990. However, the burden of PCOS-associated CVD varies widely by region; for instance, nearly 1.49% of CVD new cases were attributed to PCOS in North America. Meanwhile, the East Asia & Pacific region had the highest PCOS-associated new CVD case, and the South Asia experienced the highest increase in age-standardised incidence rates of CVD due to PCOS. Notably, we found higher worldwide PAFs, and annual increase ASIR than that in all-age group women. This result suggests that premature CVD in women with PCOS under 55 years deserve more attention.

A simple fabrication of liquid-like polydimethylsiloxane coating for resisting ice adhesion.

The rapid realization of efficient anti-icing coatings on diverse substrates is of vital value for practical applications. However, current approaches for rapid preparations of anti-icing coatings are still deficient regarding their surface universality and accessibility. Here, we report a simple processing approach to rapidly form icephobic liquid-like polydimethylsiloxane (PDMS) brushes on various substrates, including metals, ceramics, glass, and plastics. A poly(dimethylsiloxane), trimethoxysilane is applied as a reactant under the catalysis of a minimal amount of acid formed by hydrolysis of dichlorodimethylsilane. With such an advantage, this approach is approved to be applicable of coating metal surfaces with less corrosion. The distinctive flexibility of the PDMS chains provides a liquid-like property to the coating showing low contact angle hysteresis and ice adhesion strength. Notably, the ice adhesion strength remains similar across a wide temperature window, from -70 to -10 °C, with a value of 18.4 kPa. The PDMS brushes demonstrate perfect capability for resisting acid and alkali corrosions, ultra-violet degradation, and even tens of icing/deicing cycles. Moreover, the liquid-like coating can also form at supercooling conditions, such as -20 °C, and shows an outstanding anti-icing/deicing performance, which meets the in situ coating reformation requirement under extreme conditions when it is damaged. This instantly forming anti-icing material will benefit from resisting instantaneous ice accretion on surfaces under extremely cold conditions.

Enhanced brain distribution of Ginsenoside F1 via intranasal administration in combination with absorption enhancers.

Ginsenoside F1 (GF1) is a potential drug candidate for the treatment of Alzheimer's disease. Nevertheless, its low oral bioavailability and poor solubility limit clinical application. By utilizing either a direct or indirect approach, intranasal administration is a non-invasive drug delivery method that can deliver drugs to the brain rapidly. But large molecule drug delivered to the brain through intranasal administration may be insufficient to reach required concentration for therapeutic effect. In this study, using GF1 as a model drug, the feasibility of intranasal administration in combination with absorption enhancers to increase brain distribution of GF1 was explored. First of all, the appropriate absorption enhancers were screened by in situ nasal perfusion study. GF1-HP-ß-CD inclusion complex was prepared and characterized. Thereafter, in vivo absorption of GF1 after intranasal or intravenous administration of its inclusion complex with/without absorption enhancers was investigated, and safety of the formulations was evaluated. The results showed that 2% Solutol HS 15 was a superior absorption enhancer. HP-ß-CD inclusion complex improved GF1 solubility by 150 fold. Following intranasal delivery, the absolute bioavailability of inclusion complex was 46%, with drug brain targeting index (DTI) 247% and nose-to-brain direct transport percentage (DTP) 58%. Upon further addition of 2% Solutol HS 15, the absolute bioavailability was increased to 75%, with DTI 315% and DTP 66%. Both nasal cilia movement and biochemical substances (total protein and lactate dehydrogenase) leaching studies demonstrated 2% Solutol HS 15 was safe to the nasal mucosa. In conclusion, intranasal administration combining with safe absorption enhancers is an effective strategy to enhance drug distribution in the brain, showing promise for treating disorders related to the central nervous system.

Rheological properties and microstructure of wheat flour dough systems with enzyme-hydrolyzed mashed potatoes.

The interest in incorporating potatoes into wheat dough is increasing. However, potatoes exhibit significant viscosity during thermal processing, affecting product processing and quality. This study aims to find an effective method to reduce the viscosity of mashed potatoes. We aimed to compare the effects of different enzymes (α-amylase, ß-amylase, and flavourzyme) and concentrations (0.01%, 0.05%, and 0.1%) on the micromorphology and rheological properties of mashed potatoes and potato-wheat dough. The impact of flavourzyme was the most significant (p<0.05). When enzyme concentration increased, viscosity decreased, and the degree of structural damage, indicated by increased porosity. Notably, the addition of flavourzyme can increase the content of sweet and umami free amino acids, improving the flavor of mashed potatoes. The scanning electron microscopy and confocal laser scanning microscopy images of potato-wheat dough revealed that enzyme-hydrolyzed mashed potatoes had improved homogeneity, reestablished the dough continuity, and strengthened the three-dimensional structure comprising proteins and starch. Notably, flavourzyme demonstrated the most significant effect on enhancing the protein-starch network structure. This was attributed to the exposure of functional groups resulting from protein hydrolysis, facilitating interaction with starch molecules. Our findings indicate that the addition of 0.1% flavourzyme (500 LAPU/g, pH 5.5, 55 ± 2°C, 30 min treated) was the most effective in reducing viscosity and reconstructing the gluten network. Enzymatic hydrolysis plays a vital role in the production of high-quality potato products, with particular importance in the baking industry, where flavourzyme exhibits significant potential. PRACTICAL APPLICATION: Enzymatic hydrolysis plays a vital role in the production of high-quality potato products, with particular importance in the baking industry, where flavourzyme exhibits significant potential.

Reversal of Pulmonary Hypertension in a Human-Like Model: Therapeutic Targeting of Endothelial DHFR.

BACKGROUND: Pulmonary hypertension (PH) is a progressive disorder characterized by remodeling of the pulmonary vasculature and elevated mean pulmonary arterial pressure, resulting in right heart failure. METHODS: Here, we show that direct targeting of the endothelium to uncouple eNOS (endothelial nitric oxide synthase) with DAHP (2,4-diamino 6-hydroxypyrimidine; an inhibitor of GTP cyclohydrolase 1, the rate-limiting synthetic enzyme for the critical eNOS cofactor tetrahydrobiopterin) induces human-like, time-dependent progression of PH phenotypes in mice. RESULTS: Critical phenotypic features include progressive elevation in mean pulmonary arterial pressure, right ventricular systolic blood pressure, and right ventricle (RV)/left ventricle plus septum (LV+S) weight ratio; extensive vascular remodeling of pulmonary arterioles with increased medial thickness/perivascular collagen deposition and increased expression of PCNA (proliferative cell nuclear antigen) and alpha-actin; markedly increased total and mitochondrial superoxide production, substantially reduced tetrahydrobiopterin and nitric oxide bioavailabilities; and formation of an array of human-like vascular lesions. Intriguingly, novel in-house generated endothelial-specific dihydrofolate reductase (DHFR) transgenic mice (tg-EC-DHFR) were completely protected from the pathophysiological and molecular features of PH upon DAHP treatment or hypoxia exposure. Furthermore, DHFR overexpression with a pCMV-DHFR plasmid transfection in mice after initiation of DAHP treatment completely reversed PH phenotypes. DHFR knockout mice spontaneously developed PH at baseline and had no additional deterioration in response to hypoxia, indicating an intrinsic role of DHFR deficiency in causing PH. RNA-sequencing experiments indicated great similarity in gene regulation profiles between the DAHP model and human patients with PH. CONCLUSIONS: Taken together, these results establish a novel human-like murine model of PH that has long been lacking in the field, which can be broadly used for future mechanistic and translational studies. These data also indicate that targeting endothelial DHFR deficiency represents a novel and robust therapeutic strategy for the treatment of PH.

Mechanical manipulation for ordered topological defects.

Randomly distributed topological defects created during the spontaneous symmetry breaking are the fingerprints to trace the evolution of symmetry, range of interaction, and order parameters in condensed matter systems. However, the effective mean to manipulate topological defects into ordered form is elusive due to the topological protection. Here, we establish a strategy to effectively align the topological domain networks in hexagonal manganites through a mechanical approach. It is found that the nanoindentation strain gives rise to a threefold Magnus-type force distribution, leading to a sixfold symmetric domain pattern by driving the vortex and antivortex in opposite directions. On the basis of this rationale, sizeable mono-chirality topological stripe is readily achieved by expanding the nanoindentation to scratch, directly transferring the randomly distributed topological defects into an ordered form. This discovery provides a mechanical strategy to manipulate topological protected domains not only on ferroelectrics but also on ferromagnets/antiferromagnets and ferroelastics.

Single-shot digital optical fluorescence phase conjugation through forward multiple-scattering samples.

Aberrations and multiple scattering in biological tissues critically distort light beams into highly complex speckle patterns. In this regard, digital optical phase conjugation (DOPC) is a promising technique enabling in-depth focusing. However, DOPC becomes challenging when using fluorescent guide stars for four main reasons: the low photon budget available, the large spectral bandwidth of the fluorescent signal, the Stokes shift between the emission and the excitation wavelength, and the absence of reference beam preventing holographic measurement. Here, we demonstrate the possibility to focus a laser beam through multiple-scattering samples by measuring speckle fields in a single acquisition step with a reference-free, high-resolution wavefront sensor. By taking advantage of the large spectral bandwidth of forward multiply scattering samples, digital fluorescence phase conjugation is achieved to focus a laser beam at the excitation wavelength while measuring the broadband speckle field arising from a micrometer-sized fluorescent bead.

A Comparison of the Decline in Glomerular Filtration Rate between Elderly Patients with Diabetes and those without Diabetes in Southwest China.

OBJECTIVE: To investigate the effect of high blood glucose on the decline in the estimated glomerular filtration rate (eGFR) in the elderly. METHODS: We compared the decline in eGFR of diabetic and non-diabetic groups in the noninterventional state and analyzed the effect of hyperglycemia on the decline in eGFR among the elderly in a retrospective analysis of 1,223 cases of elderly people aged 65 years or older with a 4-year follow-up period. RESULTS: The prevalence of diabetes in the elderly increased significantly from 12.67% in 2017 to 16.68% in 2021. The rate of decline in eGFR in patients with diabetes was higher than in the population without diabetes, at 9.29% and 5.32%, respectively (both p <0.05). CONCLUSION: The results of this study revealed that the prevalence of diabetes in the elderly increased significantly, and there is a more rapid decrease in the eGFR levels in those with diabetes than those without diabetes.