Quantifying depressive symptoms on incidence of common chronic diseases and multimorbidity patterns in middle-aged and elderly Chinese adults.

BACKGROUND: Depressive symptoms are highly prevalent and increase risks of various morbidities. However, the extent to which depressive symptoms could account for incidence of these chronic conditions, in particular multimorbidity patterns, remains to be examined and quantified. METHODS: For this cohort analysis, we included 9024-14,093 participants aged 45 years and older from the China Health and Retirement Longitudinal Study (CHARLS). Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the longitudinal associations between depressive symptoms and 13 common chronic diseases and 4 multimorbidity patterns. Population attributable fractions (PAFs) combining the information on both exposure prevalence and risk association were estimated to quantify the magnitude of the burden of these conditions attributable to depressive symptoms. RESULTS: Depressive symptoms were associated with increased risks of liver disease, stroke, heart problem, asthma, diabetes, arthritis, kidney disease, chronic lung disease, digestive disease, dyslipidemia, and memory-related disease, and the adjusted HRs (95% CIs) and PAFs (95% CIs) ranged from 1.15 (1.05-1.26) to 1.64 (1.38-1.96) and 5% (0-10%) to 17% (6-28%), respectively. In addition, individuals with depressive symptoms had elevated risks of the cardiometabolic-cancer pattern, the cerebrovascular-memory pattern, the articular-visceral organ pattern, and the respiratory pattern, with respective HRs (95% CIs) of 1.26 (1.11-1.42), 1.34 (1.07-1.69), 1.45 (1.29-1.63), and 2.01 (1.36-2.96), and respective PAFs (95% CIs) of 5% (0-10%), 8% (-4-21%), 12% (7-17%), and 20% (5-35%). CONCLUSION: Depressive symptoms contribute substantially to the burden across a broad range of chronic diseases as well as different multimorbidity patterns in middle-aged and older Chinese.

Targeted inhibition of autophagy in hepatic stellate cells by hydroxychloroquine: An effective therapeutic approach for the treatment of liver fibrosis.

BACKGROUND AND PURPOSE: Liver fibrosis is a wound-healing reaction which is the main cause of chronic liver diseases worldwide. The activated hepatic stellate cell (aHSC) is the main driving factor in the development of liver fibrosis. Inhibiting autophagy of aHSC can prevent the progression of liver fibrosis, but inhibiting autophagy of other liver cells has opposite effects. Hence, targeted inhibition of autophagy in aHSC is quite necessary for the treatment of liver fibrosis, which prompts us to explore the targeted delivery system of small molecule autophagy inhibitor hydroxychloroquine (HCQ) that can target aHSC and alleviate the liver fibrosis. METHODS: The delivery system of HCQ@retinol-liposome nanoparticles (HCQ@ROL-LNPs) targeting aHSC was constructed by the film dispersion and pH-gradient method. TGF-ß-induced HSC activation and thioacetamide (TAA)-induced liver fibrosis mice model were established, and the targeting ability and therapeutic effect of HCQ@ROL-LNPs in liver fibrosis were studied subsequently in vitro and in vivo. RESULTS: HCQ@ROL-LNPs have good homogeneity and stability. They inhibited the autophagy of aHSC selectively by HCQ and reduced the deposition of extracellular matrix (ECM) and the damage to other liver cells. Compared with the free HCQ and HCQ@LNPs, HCQ@ROL-LNPs had good targeting ability, showing enhanced therapeutic effect and low toxicity to other organs. CONCLUSION: Construction of HCQ@ROL-LNPs delivery system lays a theoretical and experimental foundation for the treatment of liver fibrosis and promotes the development of clinical therapeutic drugs for liver diseases.

Exploring the effect of different application rates of biochar on the accumulation of nutrients and growth of flue-cured tobacco (Nicotiana tabacum).

Background: Biochar application has become one of the most potential tools to improve soil fertility and plant growth for sustainable and eco-friendly agriculture. However, both positive and negative effects of biochar application have been recorded on plant growth and soil fertility. Methods: This study investigated the impact of different application rates (0, 600, 900, 1200, and 1800 kg/ha) of biochar on the soil nutrient contents, accumulation of nutrients and dry matter in different plant parts, and growth of flue-cured tobacco plants under field conditions. Results: Results demonstrated that soil organic carbon pool and carbon/nitrogen ratio were increased proportionally with the increasing dosage of biochar, 25.54 g/kg and 14.07 g/kg compared with control 17 g/kg and 10.13 g/kg, respectively. The contents of soil total nitrogen were also significantly increased after biochar application in the middle (1.77 g/kg) and late-growth (1.54 g/kg) stages of flue-cured tobacco than in control (1.60 g/kg and 1.41 g/kg, respectively). The contents of soil nitrate nitrogen were also higher under low (600 and 900 kg/ha) application rates of biochar and reduced when higher (1200 and 1800 kg/ha) dosages of biochar were applied. However, it was observed that varying application rates of biochar had no impact on soil ammonium nitrogen content during the growth period of flue-cured tobacco plants. The nutrient accumulation (N, P, K) in different parts of flue-cured tobacco plants was significantly increased under a low application rate of biochar, which enhanced the soil and plant analyzer development values, effective leaves number, growth, dry matter accumulation, and leaf yield of flue-cured tobacco. In contrast, the high biochar application rate (1200 and 1800 kg/ha) negatively impacted nutrient accumulation and growth of flue-cured tobacco. Conclusion: Conclusively, the optimum application of biochar (600 and 900 kg/ha) is beneficial for plant growth, soil fertility, accumulation of nutrients, and dry matter in different plant parts. However, excessive biochar application (> 900 kg/ha) could inhibit flue-cured tobacco plant growth. This study provides a theoretical foundation for biochar application in tobacco and other crop production to obtain agricultural sustainability and economic stability.

Processed Polygonatum cyrtonema Hua attenuates postpartum depression in rat model by regulating monoamines and hormones.

Background: Polygonatum cyrtonema Hua is a traditional Chinese medicinal food herb which can regulate the liver and Qi, nourish the heart and blood, moisten the lungs and nourish the kidneys with the potential to treat emotional diseases. However, few studies have explored the effects of Polygonatum cyrtonema Hua on postpartum depression. Therefore, we investigated whether processed Polygonatum cyrtonema Hua could improve postpartum depression in rat models by regulating monoamines and hormones. Methods: Female Sprague-Dawley rats were randomized into normal control (0.9%Nacl), Sham operation (0.9%Nacl), postpartum depression model (0.9%Nacl), fluoxetine (2.5 mg/kg Fluoxetine), low, medium and high dose of processed Polygonatum cyrtonema Hua (2.5 g/kg, 5 g/kg, 10 g/kg) groups. Rats in these groups received drug intervention, and then subjected to Open-field test and Forced swimming test. Brain tissues and serum samples were collected and used to quantify levels of monoamines, hypothalamic-pituitary-adrenal axis and serum Estradiol. The status of neuronal cells in hippocampus 1 region was examined through hematoxylin-eosin staining, whereas expression of estrogen receptor α and ß was detected by immunohistochemistry. Results: Rats in the model group showed decreased mobility time, the disorder of neuronal cells in hippocampus 1 area, and decreased concentration of 5-hydroxytryptamine and dopamine in brain tissue, norepinephrine and estradiol in serum as well as estrogen receptor α and ß expression. They also exhibited increased adrenocorticotropic hormone, corticosterone and corticotropin releasing hormone in serum. However, the treatment with processed Polygonatum cyrtonem Hua or fluoxetine reversed the above abnormalities. Conclusion: The H group showed significant improvement in postpartum depression in rats, and processed Polygonatum cyrtonema Hua can be used as a developing drug for the prevention or treatment of depression.

Research progress of dydrogesterone in the treatment of endometriosis.

Endometriosis is a common gynecological disease among women of reproductive age. It is a chronic estrogen and progestin related inflammatory disease. At present, the main treatments for endometriosis are drug therapy and surgery. In drug therapy, progesterone is listed as the first-line recommendation in multinational guidelines. Dydrogesterone, as an oral reversal progesterone, can slow down the metabolism of progesterone, inhibit angiogenesis and extracellular matrix degradation to inhibit the proliferation of the ectopic endometrium, induce the atrophy of the ectopic endometrium through the pro-apoptotic pathway, and treat endometriosis through multiple mechanisms of regulating inflammatory factors to reduce inflammation. Clinically, dydrogesterone treatment of endometriosis can relieve patients' symptoms, promote fertility, be used in combination, and is safe. This article will review the mechanism and clinical application of dydrogesterone in the treatment of endometriosis.

Histone demethylase KDM5D represses the proliferation, migration and invasion of hepatocellular carcinoma through the E2F1/TNNC1 axis.

OBJECTIVE: This study focused on investigating the mechanism in which the KDM5D/E2F1/TNNC1 axis affected hepatocellular carcinoma (HCC) development. METHODS: At first, we determined HCC cell proliferation, migration, invasion, and apoptosis, as well as SOD activity, MDA content, and ROS level. ChIP assay was subsequently conducted to examine H3K4me3 modification in the E2F1 promoter region and the binding of E2F1 to the TNNC1 promoter region after KDM5D overexpression. Meanwhile, we performed western blot for testing KDM5D, H3K4me3, and E2F1 expression after KDM5D overexpression in Huh-7 cells. The binding of transcription factor E2F1 to the TNNC1 promoter region was assessed by dual luciferase reporter gene assay. We further observed the tumor growth ability in nude mice transplanted tumor models. RESULTS: Overexpressed KDM5D suppressed HCC proliferation, migration, and invasion, promoted the apoptosis, suppressed SOD activity, elevated MDA content and ROS level, and promoted ferroptosis. KDM5D suppressed H3K4me3 modification in the E2F1 promoter region and suppressed E2F1 expression in HCC cells. Reduced KDM5D, H3K4me3, and E2F1 expression was found after KDM5D overexpression in Huh-7 cells. Overexpressing E2F1 reversed the inhibitory effects of KDM5D on HCC cell proliferative, migratory, and invasive behaviors. KDM5D repressed TNNC1 transcription by inhibiting E2F1 binding to the TNNC1 promoter. In vivo KDM5D overexpression inhibited HCC development via the E2F1/TNNC1 axis. CONCLUSION: KDM5D inhibits E2F1 expression by suppressing H3K4me3 modification in the E2F1 promoter region, which in turn suppresses the binding of E2F1 to the TNNC1 promoter region, thus leading to the inhibition of HCC development.

Reactive Oxygen-Correlated Photothermal Imaging of Smart COF Nanoreactors for Monitoring Chemodynamic Sterilization and Promoting Wound Healing.

Chemodynamic therapy (CDT) has emerged as a promising approach for treating infected diabetic wounds, while reliable imaging technology for simultaneous monitoring of ROS and therapeutic processes is still a formidable challenge. Herein, smart covalent organic framework (COF) nanoreactors (COF NRs) are constructed by hyaluronic acid (HA) packaged glucose oxidase (GOx) covalently linked Fe-COF for diabetic wound healing. Upon the breakdown of the HA protective layer, GOx consumes glucose to produce gluconic acid and hydrogen peroxide (H2 O2 ), resulting in decreased local pH and H2 O2 supplementation. Density functional theory (DFT) calculations show that Fe-COF has high catalytic activity towards H2 O2 , leading to in situ generation of hydroxyl radicals (·OH) for sterilization, and the localized downregulation of glucose effectively improved the microenvironment of diabetic wounds. Meanwhile, based on the near-infrared photothermal imaging of oxidized 3,3',5,5'-tetramethylbenzidine (oxTMB), the authors showed that TMB can be applied for the point-of-care testing of ·OH and glucose, and assessing the sterilization progress in vivo. More significantly, the facile photothermal signaling strategy can be extended to monitor various ROS-mediated therapeutic systems, enabling accurate prediction of treatment outcomes.

Activation of Hypoxia Inducible Factor-1 Alpha-Mediated DNA Methylation Enzymes (DNMT3a and TET2) Under Hypoxic Conditions Regulates S100A6 Transcription to Promote Lung Cancer Cell Growth and Metastasis.

Aims: This research was aimed at investigating the effects of hypoxia inducible factor-1 alpha (HIF-1α)-mediated DNA methylation enzymes (ten-eleven translocase-2 [TET2] and DNA methyltransferase-3a [DNMT3a]) under hypoxic conditions on S100A6 transcription, thereby promoting the growth and metastasis of lung cancer cells. Methods: The expression of HIF-1α or S100A6 in lung cancer cells was interfered with under normoxic and hypoxic conditions, and the cell proliferative, migratory, and invasive properties were assessed. The mechanism of HIF-1α-regulated TET2 and DNMT3 effects on S100A6 transcription under hypoxic conditions was further investigated. Results: Functionally, S100A6 over-expression promoted lung cancer cell proliferation and metastasis. S100A6 over-expression reversed the inhibitory effects of HIF-1α interference on the proliferation and metastasis of lung cancer cells. S100A6 was induced to express in an HIF-1α-dependent manner under hypoxic conditions, and silencing S100A6 or HIF-1α suppressed lung cancer cell proliferation and metastasis under hypoxic conditions. Further, The Cancer Genome Atlas-lung adenocarcinoma database analysis revealed that S100A6 mRNA levels had a negative correlation with methylation levels. Mechanistically, CpG hypomethylation status in the S100A6 promoter hypoxia response element had an association with HIF-1α induction. TET2 was enriched in S100A6 promoter region of lung cancer cells under hypoxic conditions, whereas DNMT3a enrichment was reduced in S100A6 promoter region. HIF-1α-mediated S100A6 activation was linked to DNMT3a-associated epigenetic inactivation and TET2 activation. Innovation: The activation of HIF-1α-mediated DNA methylation enzymes under hypoxic conditions regulated S100A6 transcription, thereby promoting lung cancer cell growth and metastasis. Conclusion: In lung cancer progression, hypoxia-induced factor HIF-1α combined with DNA methylation modifications co-regulates S100A6 transcriptional activation and promotes lung cancer cell growth and metastasis.

Effects of atropine eyedrops at ten different concentrations for myopia control in children: A systematic review on meta-analysis.

PURPOSE: To estimate the effect of atropine eyedrops at different concentrations for myopia control in children. METHODS: We conducted a Bayesian random-effects network meta-analysis based on randomized controlled trials (RCT). Primary outcomes include changes in spherical equivalent error (SER) and changes in axial length (AL), mean difference (MD) together with 95% credible interval (CrI) were used to evaluate the efficacy. RESULTS: 28 RCTs (6608 children) were included in this review. Comparing ten atropine eyedrops (0.0025%, 0.005%, 0.01%, 0.02%, 0.025%, 0.05%, 0.1%, 0.25%, 0.5% and 1% concentrations) with the placebo, the MDs and 95%CrIs of changes in SER are -0.006 (-0.269, 0.256) D, 0.216 (-0.078, 0.508) D, 0.146 (0.094, 0.199) D, 0.167 (0.039, 0.297) D, 0.201 (0.064, 0.341) D, 0.344 (0.251, 0.440) D, 0.255 (0.114, 0.396) D, 0.296 (0.140, 0.452) D, 0.331 (0.215, 0.447) D, and 0.286 (0.195, 0.337) D, respectively. The MDs and 95%CrIs of changes in AL are -0.048 (-0.182, 0.085) mm, -0.078 (-0.222, 0.066) mm, -0.095 (-0.130, -0.060) mm, -0.096 (-0.183, -0.009) mm, -0.083 (-0.164, -0.004) mm, -0.114 (-0.176, -0.056) mm, -0.134 (-0.198, -0.032) mm, -0.174 (-0.315, -0.061) mm, -0.184 (-0.291, -0.073) mm, and -0.171 (-0.203, -0.097) mm, respectively.Whether evaluated by SER or AL, 1% concentration ranks first in efficacy, but the risk of photophobia is 17 times higher than 0.01% concentration. CONCLUSIONS: 0.01% or higher concentration atropine eyedrops are effective for myopia control, while 0.0025% and 0.005% concentrations may not. As the concentration increases, the effect tends to increase, 1% concentration may have the strongest effect.

Metabolomics on depression: A comparison of clinical and animal research.

BACKGROUND: Depression is a major cause of suicide and mortality worldwide. This study aims to conduct a systematic review to identify metabolic biomarkers and pathways for major depressive disorder (MDD), a prevalent subtype of clinical depression. METHODS: We searched for metabolomics studies on depression published between January 2000 and January 2023 in the PubMed and Web of Science databases. The reported metabolic biomarkers were systematically evaluated and compared. Pathway analysis was implemented using MetaboAnalyst 5.0. RESULTS: We included 26 clinical studies on MDD and 78 metabolomics studies on depressive-like animal models. A total of 55 and 77 high-frequency metabolites were reported consistently in two-thirds of clinical and murine studies, respectively. In the comparison between murine and clinical studies, we identified 9 consistently changed metabolites (tryptophan, tyrosine, phenylalanine, methionine, fumarate, valine, deoxycholic acid, pyruvate, kynurenic acid) in the blood, 1 consistently altered metabolite (indoxyl sulfate) in the urine and 14 disturbed metabolic pathways in both types of studies. These metabolic dysregulations and pathways are mainly implicated in enhanced inflammation, impaired neuroprotection, reduced energy metabolism, increased oxidative stress damage and disturbed apoptosis, laying solid molecular foundations for MDD. LIMITATIONS: Due to unavailability of original data like effect-size results in many metabolomics studies, a meta-analysis cannot be conducted, and confounding factors cannot be fully ruled out. CONCLUSIONS: This systematic review delineated metabolic biomarkers and pathways related to depression in the murine and clinical samples, providing opportunities for early diagnosis of MDD and the development of novel diagnostic targets.

Mapping of cytosol-facing organelle outer membrane proximity proteome by proximity-dependent biotinylation in living Arabidopsis cells.

The cytosol-facing outer membrane (OM) of organelles communicates with other cellular compartments to exchange proteins, metabolites, and signaling molecules. Cellular surveillance systems also target OM-resident proteins to control organellar homeostasis and ensure cell survival under stress. However, the OM proximity proteomes have never been mapped in plant cells since using traditional approaches to discover OM proteins and identify their dynamically interacting partners remains challenging. In this study, we developed an OM proximity labeling (OMPL) system using biotin ligase-mediated proximity biotinylation to identify the proximity proteins of the OMs of mitochondria, chloroplasts, and peroxisomes in living Arabidopsis (Arabidopsis thaliana) cells. Using this approach, we mapped the OM proximity proteome of these three organelles under normal conditions and examined the effects of the ultraviolet-B (UV-B) or high light (HL) stress on the abundances of OM proximity proteins. We demonstrate the power of this system with the discovery of cytosolic factors and OM receptor candidates potentially involved in local protein translation and translocation. The candidate proteins that are involved in mitochondrion-peroxisome, mitochondrion-chloroplast, or peroxisome-chloroplast contacts, and in the organellar quality control system are also proposed based on OMPL analysis. OMPL-generated OM proximity proteomes are valuable sources of candidates for functional validation and suggest directions for further investigation of important questions in cell biology.

Concordance between reflectance confocal microscopy and histopathology for the diagnosis of acral lentiginous melanoma.

BACKGROUND: Acral lentiginous melanoma (ALM) is a highly malignant and invasive type of melanoma with unique locations of onset. Its incidence is increasing and early diagnosis is challenging. Reflectance confocal microscopy (RCM) is a non-invasive technique that provides an accurate image of tissue pathology. There are few reports on the use of RCM for the assessment of ALM. MATERIALS AND METHODS: In this retrospective study, data from 31 patients with a clinical diagnosis of ALM were collected. RCM image features were compared with histopathological findings to determine the concordance between the two methods. The sensitivity, specificity, positive predictive value, and negative predictive value of RCM for the diagnosis of ALM were evaluated. RESULTS: RCM and histopathology findings were concordant in 29 of 31 patients (93.5%). There were no false-negative results, although there were two false positives in RCM diagnosis. The sensitivity of RCM for diagnosing ALM was 100%, specificity was 50%, positive predictive value was 93.1%, and negative predictive value was 100%. CONCLUSIONS: RCM showed substantial concordance with histopathology in the diagnosis of ALM. It is a reliable and valuable non-invasive diagnostic tool that holds promise for the early diagnosis of ALM.

Fine Tuning Water States in Hydrogels for High Voltage Aqueous Batteries.

Hydrogels are widely used as quasi-solid-state electrolytes in aqueous batteries. However, they are not applicable in high-voltage batteries because the hydrogen evolution reaction cannot be effectively suppressed even when water is incorporated into the polymer network. Herein, by profoundly investigating the states of water molecules in hydrogels, we designed supramolecular hydrogel electrolytes featuring much more nonfreezable bound water and much less free water than that found in conventional hydrogels. Specifically, two strategies are developed to achieve this goal. One strategy is adopting monomers with a variety of hydrophilic groups to enhance the hydrophilicity of polymer chains. The other strategy is incorporating zwitterionic polymers or polymers with counterions as superhydrophilic units. In particular, the nonfreezable bound water content increased from 0.129 in the conventional hydrogel to >0.4 mg mg-1 in the fabricated hydrogels, while the free water content decreased from 1.232 to ∼0.15 mg mg-1. As a result, a wide electrochemical stability window of up to 3.25 V was obtained with the fabricated hydrogels with low concentrations of incorporated salts and enhanced hydrophilic groups or superhydrophilic groups. The ionic conductivities achieved with our developed hydrogel electrolytes were much higher than those in the conventional highly concentrated salt electrolytes, and their cost is also much lower. The designed supramolecular hydrogel electrolytes endowed an aqueous K-ion battery (AKIB) system with a high voltage plateau of 1.9 V and contributed to steady cycling of the AKIB for over 3000 cycles. The developed supramolecular hydrogel electrolytes are also applicable to other batteries, such as aqueous lithium-ion batteries, hybrid sodium-ion batteries, and multivalent-ion aqueous batteries, and can achieve high voltage output.

Safety, pharmacokinetics and pharmacodynamics of HWH486 capsules in healthy adults: A randomized, double-blind, placebo-controlled, phase I dose-escalation study.

OBJECTIVES: HWH486 inhibits Bruton's tyrosine kinase and therefore shows promise as a treatment against rheumatoid arthritis and chronic spontaneous urticaria. This phase I trial assessed tolerability, safety, pharmacokinetics and pharmacodynamics of a single oral dose of HWH486 capsules in healthy adults. METHODS: A single-center, randomized, double-blind, placebo-controlled, dose-escalation study from 10 to 800 mg was conducted in 96 healthy Chinese adults, of whom 80 received HWH486 and 16 received placebo. RESULTS: A total of 96 subjects were enrolled, and all completed the study. In the HWH486 group, mean Tmax ranged from 1.03 to 2.00 h, and mean T1/2 ranged from 0.85 to 8.67 h across the dose range from 10 to 800 mg. Mean Cmax increased linearly with dose, while mean AUC0-t increased non-linearly. Occupancy of Bruton's tyrosine kinase peaked within 0.50-4.00 h after administration across the dose groups, and the delay until peak occupancy decreased with increasing dose. Twenty-five subjects (31.25 %) in the HWH486 group experienced 35 treatment-emergent adverse events, while four subjects (25.00 %) in the placebo group experienced eight such events. CONCLUSIONS: HWH486 is well tolerated and safe in healthy adults, in whom it can strongly bind Bruton's tyrosine kinase. These findings justify clinical studies of HWH486 efficacy against autoimmune diseases.

Efficacy and safety of CM310 in moderate-to-severe atopic dermatitis: A multicenter, randomized, double-blind, placebo-controlled phase 2b trial.

BACKGROUND: Atopic dermatitis (AD) affects approximately 10% of adults worldwide. CM310 is a humanized monoclonal antibody targeting interleukin-4 receptor alpha that blocks interleukin-4 and interleukin-13 signaling. This trial aimed to evaluate the efficacy and safety of CM310 in Chinese adults with moderate-to-severe AD. METHODS: This multicenter, randomized, double-blind, placebo-controlled, phase 2b trial was conducted in 21 medical institutions in China from February to November 2021. Totally 120 eligible patients were enrolled and randomized (1:1:1) to receive subcutaneous injections of 300 mg CM310, 150 mg CM310, or placebo every 2 weeks for 16 weeks, followed by an 8-week follow-up period. The primary endpoint was the proportion of patients achieving ≥75% improvement in the Eczema Area and Severity Index (EASI-75) score from baseline at week 16. Safety and pharmacodynamics were also studied. RESULTS: At week 16, the proportion of EASI-75 responders from baseline was significantly higher in the CM310 groups (70% [28/40] for high-dose and 65% [26/40] for low-dose) than that in the placebo group (20%[8/40]). The differences in EASI-75 response rate were 50% (high vs . placebo, 95% CI 31%-69%) and 45% (low vs . placebo, 95% CI 26%-64%), with both P values <0.0001. CM310 at both doses also significantly improved the EASI score, Investigator's Global Assessment score, daily peak pruritus Numerical Rating Scale, AD-affected body surface area, and Dermatology Life Quality Index compared with placebo. CM310 treatment reduced levels of thymus and activation-regulated chemokine, total immunoglobulin E, lactate dehydrogenase, and blood eosinophils. The incidence of treatment-emergent adverse events (TEAEs) was similar among all three groups, with the most common TEAEs reported being upper respiratory tract infection, atopic dermatitis, hyperlipidemia, and hyperuricemia. No severe adverse events were deemed to be attributed to CM310. CONCLUSION: CM310 at 150 mg and 300 mg every 2 weeks demonstrated significant efficacy and was well-tolerated in adults with moderate-to-severe AD.

Quantitative 17 O MRSI of myocardial oxygen metabolic rate, blood flow, and oxygen extraction fraction under normal and high workload conditions.

PURPOSE: The heart is a highly aerobic organ consuming most of the oxygen the body in supporting heart function. Quantitative imaging of myocardial oxygen metabolism and perfusion is essential for studying cardiac physiopathology in vivo. Here, we report a new imaging method that can simultaneously assess myocardial oxygen metabolism and blood flow in the rat heart. METHODS: This novel method is based on the 17 O-MRSI combined with brief inhalation of 17 O-isotope labeled oxygen gas for quantitative imaging of myocardial metabolic rate of oxygen consumption (MVO2 ), myocardial blood flow (MBF), and oxygen extraction fraction (OEF). We demonstrate this imaging method under basal and high workload conditions in rat hearts at 9.4 T. RESULTS: We show that this 17 O MRSI-based approach can directly measure and image MVO2 (1.35-4.06 µmol/g/min), MBF (0.49-1.38 mL/g/min), and OEF (0.33-0.44) in the heart of anesthetized rat under basal and high workload (21.6 × 103 -56.7 × 103 mmHg • bpm) conditions. Under high workload condition, MVO2 and MBF values in healthy rats approximately doubled, whereas OEF remained unchanged, indicating a strong coupling between myocardial oxygen metabolic demand and supply through blood perfusion. CONCLUSION: The 17 O-MRSI method has been used to simultaneously image the myocardial metabolic rate of oxygen consumption, blood flow, and oxygen extraction fraction in small animal hearts, which are sensitive to the physiological changes induced by high workload. This approach could provide comprehensive measures that are critical for studying myocardial function in normal and diseased states and has a potential for translation.

A holistic framework of biochar-augmented cementitious products and general applications: Technical, environmental, and economic evaluation.

In the context of the circular economy, the development of innovative and low-carbon concrete that incorporates different kinds of waste materials is gaining attention among the research community, regulatory agencies, and policymakers. These materials can be incorporated into concrete mixtures as aggregates or as fillers for improvement of product properties. This study aims to identify reliable designs for biochar-augmented cementitious products and general applications through technical, environmental, and economic assessments. The outcomes demonstrate that 5 wt% biochar addition could enhance the compressive strength of the final products. Using biochar, together with other recycled materials, can enormously reduce the environmental impacts, especially for global warming, enabling biochar-augmented cementitious products and general application as carbon-negative resources. The highest GWP reduction reached -720 kg CO2/tonne, equal to a 200% saving. A high quantity of biochar could be included in several specific applications (up to 60 wt%). The economic assessment highlights that the proposed designs are cost-effective and carbon tax can be significantly reduced. Carbon credits can also be earned for some carbon-negative designs. These findings can serve to mitigate GHG emissions and provide decision-makers with a reliable and holistic framework towards the goal of carbon neutrality.

Interfacial Modification of Ga-Substituted Li7La3Zr2O12 against Li Metal via a Simple Doping Method.

Garnet Li7La3Zr2O12 (LLZO) is considered a promising solid electrolyte for all-solid-state lithium-ion batteries due to its outstanding performance in which Ga-doped LLZO particularly exhibits excellent ionic conductivity. However, the application of Ga-doped LLZO is limited by the interfacial instability between Ga-doped LLZO and Li metal. In this study, Ga3+- and Sb5+-codoped LLZO is prepared using a conventional solid-state reaction method, and the effects of dual-doping on the crystal structure, microstructure, conductivity of LLZO, and battery cycle stability are investigated. The results demonstrate that the introduction of an appropriate amount of Sb5+ into Ga3+-stabilized cubic-phase LLZO promotes grain contact and enhances the total ionic conductivity. The optimized Li6.3Ga0.2La3Zr1.9Sb0.1O12 solid electrolyte exhibits the highest total ionic conductivity of 4.65 × 10-4 S cm-1 at room temperature. Additionally, the introduction of Sb5+ suppresses the formation of the LiGaO2 impurity phase, thereby improving the interface stability between Ga-doped LLZO and the Li metal. The assembled Li||Ga,Sb0.1-LLZO||Li symmetric cell demonstrates stable cycling for 500 h at room temperature under a current density of 0.13 mA cm-2. The Li||Ga,Sb0.1-LLZO||LiFePO4 full cell delivers a reversible capacity of about 140 mA h g-1, exhibiting negligible decay after 50 cycles. These findings suggest that the application of Ga-doped LLZO in all-solid-state lithium-ion batteries holds great promise by simply doping Zr sites with high-valence ions.

Anti-Biofilm Activity of Cocultimycin A against Candida albicans.

Candida albicans (C. albicans), the most common fungal pathogen, has the ability to form a biofilm, leading to enhanced virulence and antibiotic resistance. Cocultimycin A, a novel antifungal antibiotic isolated from the co-culture of two marine fungi, exhibited a potent inhibitory effect on planktonic C. albicans cells. This study aimed to evaluate the anti-biofilm activity of cocultimycin A against C. albicans and explore its underlying mechanism. Crystal violet staining showed that cocultimycin A remarkably inhibited biofilm formation in a dose-dependent manner and disrupted mature biofilms at higher concentrations. However, the metabolic activity of mature biofilms treated with lower concentrations of cocultimycin A significantly decreased when using the XTT reduction method. Cocultimycin A could inhibit yeast-to-hypha transition and mycelium formation of C. albicans colonies, which was observed through the use of a light microscope. Scanning electron microscopy revealed that biofilms treated with cocultimycin A were disrupted, yeast cells increased, and hypha cells decreased and significantly shortened. The adhesive ability of C. albicans cells treated with cocultimycin A to the medium and HOEC cells significantly decreased. Through the use of a qRT-PCR assay, the expression of multiple genes related to adhesion, hyphal formation and cell membrane changes in relation to biofilm cells treated with cocultimycin A. All these results suggested that cocultimycin A may be considered a potential novel molecule for treating and preventing biofilm-related C. albicans infections.

Prognostic Implications of LRP1B and Its Relationship with the Tumor-Infiltrating Immune Cells in Gastric Cancer.

BACKGROUND: Recent studies have shown that low-density lipoprotein receptor-related protein 1b (LRP1B), as a potential tumor suppressor, is implicated in the response to immunotherapy. The frequency of LRP1B mutation gene is high in many cancers, but its role in gastric cancer (GC) has not been determined. METHODS: The prognostic value of LRP1B mutation in a cohort containing 100 patients having received radical gastrectomy for stage II-III GC was explored. By analyzing the data of LRP1B mRNA, the risk score of differentially expressed genes (DEGs) between LRP1B mutation-type and wild-type was constructed based on the TCGA-STAD cohort. The infiltration of tumor immune cells was evaluated by the CYBERSORT algorithm and verified by immunohistochemistry. RESULTS: LRP1B gene mutation was an independent risk factor for disease-free survival (DFS) in GC patients (HR = 2.57, 95% CI: 1.28-5.14, p = 0.008). The Kaplan-Meier curve demonstrated a shorter survival time in high-risk patients stratified according to risk score (p < 0.0001). CYBERSORT analysis showed that the DEGs were mainly concentrated in CD4+ T cells and macrophages. TIMER analysis suggested that LRP1B expression was associated with the infiltration of CD4+ T cells and macrophages. Immunohistochemistry demonstrated that LRP1B was expressed in the tumor cells (TCs) and immune cells in 16/89 and 26/89 of the cohort, respectively. LRP1B-positive TCs were associated with higher levels of CD4+ T cells, CD8+ T cells, and CD86/CD163 (p < 0.05). Multivariate analysis showed that LRP1B-positive TCs represented an independent protective factor of DFS in GC patients (HR = 0.43, 95% CI: 0.10-0.93, p = 0.042). CONCLUSIONS: LRP1B has a high prognostic value in GC. LRP1B may stimulate tumor immune cell infiltration to provide GC patients with survival benefits.