Fluorescence and photoacoustic (FL/PA) dual-modal probe: Responsive to reactive oxygen species (ROS) for atherosclerotic plaque imaging.

Accurate and early detection of atherosclerosis (AS) is imperative for their effective treatment. However, fluorescence probes for efficient diagnosis of AS often encounter insufficient deep tissue penetration, which hinders the reliable assessment of plaque vulnerability. In this work, a reactive oxygen species (ROS) activated near-infrared (NIR) fluorescence and photoacoustic (FL/PA) dual model probe TPA-QO-B is developed by conjugating two chromophores (TPA-QI and O-OH) and ROS-specific group phenylboronic acid ester. The incorporation of ROS-specific group not only induces blue shift in absorbance, but also inhibits the ICT process of TPA-QO-OH, resulting an ignorable initial FL/PA signal. ROS triggers the convertion of TPA-QO-B to TPA-QO-OH, resulting in the concurrent amplification of FL/PA signal. The exceptional selectivity of TPA-QO-B towards ROS makes it effectively distinguish AS mice from the healthy. The NIR emission can achieve a tissue penetration imaging depth of 0.3 cm. Moreover, its PA775 signal possesses the capability to penetrate tissues up to a thickness of 0.8 cm, ensuring deep in vivo imaging of AS model mice in early stage. The ROS-triggered FL/PA dual signal amplification strategy improves the accuracy and addresses the deep tissue penetration problem simultaneously, providing a promising tool for in vivo tracking biomarkers in life science and preclinical applications.

Advances in meniscus tissue engineering: Towards bridging the gaps from bench to bedside.

Meniscus is vital for maintaining the anatomical and functional integrity of knee. Injuries to meniscus, commonly caused by trauma or degenerative processes, can result in knee joint dysfunction and secondary osteoarthritis, while current conservative and surgical interventions for meniscus injuries bear suboptimal outcomes. In the past decade, there has been a significant focus on advancing meniscus tissue engineering, encompassing isolated scaffold strategies, biological augmentation, physical stimulus, and meniscus organoids, to improve the prognosis of meniscus injuries. Despite noteworthy promising preclinical results, translational gaps and inconsistencies in the therapeutic efficiency between preclinical and clinical studies exist. This review comprehensively outlines the developments in meniscus tissue engineering over the past decade (Scheme 1). Reasons for the discordant results between preclinical and clinical trials, as well as potential strategies to expedite the translation of bench-to-bedside approaches are analyzed and discussed.

Predicting Human Subcutaneous Bioavailability of Therapeutic Monoclonal Antibodies from Systemic Clearance and Volume of Distribution.

Subcutaneous delivery of monoclonal antibody therapeutics is often preferred to intravenous delivery due to better patient compliance and overall lower cost to the healthcare system. However, the systemic absorption of biologics dosed subcutaneously is often incomplete. The aim of this work was to describe a human bioavailability prediction method for monoclonal antibodies delivered subcutaneously that utilizes intravenous pharmacokinetic parameters as input. A two-compartment pharmacokinetic model featuring a parallel-competitive absorption pathway and a presystemic metabolism pathway was employed. A training data set comprised 19 monoclonal antibodies (geometric mean bioavailability of 68%), with previously reported human pharmacokinetic parameters, while a validation set included data compiled from 5 commercial drug products (geometric mean bioavailability of 69%). A single fitted absorption rate constant, paired with compound-specific estimates of presystemic metabolism rate proportional to compound-specific systemic clearance parameters, resulted in calculations of human subcutaneous bioavailability closely mimicking clinical data in the training data set with a root-mean-square error of 5.5%. Application of the same approach to the validation data set resulted in predictions characterized by 12.6% root-mean-square error. Factors that may have impacted the prediction accuracy include a limited number of validation data set compounds and an uncertainty in the absorption rate, which were subsequently discussed. The predictive method described herein provides an initial estimate of the subcutaneous bioavailability based exclusively on pharmacokinetic parameters available from intravenous dosing.

BRCA1 promotes repair of DNA damage in cochlear hair cells and prevents hearing loss.

Cochlear hair cells (HCs) sense sound waves and allow us to hear. Loss of HCs will cause irreversible sensorineural hearing loss. It is well known that DNA damage repair plays a critical role in protecting cells in many organs. However, how HCs respond to DNA damage and how defective DNA damage repair contributes to hearing loss remain elusive.In this study, we showed that cisplatin induced DNA damage in outer hair cells (OHCs) and promoted OHC loss, leading to hearing loss in mice of either sex. Cisplatin induced the expression of Brca1, a DNA damage repair factor, in OHCs. Deficiency of Brca1 induced OHC and hearing loss, and further promoted cisplatin-induced DNA damage in OHCs, accelerating OHC loss. This study provides the first in vivo evidence demonstrating that cisplatin mainly induces DNA damage in OHCs and that BRCA1 promotes repair of DNA damage in OHCs and prevents hearing loss. Our findings not only demonstrate that DNA-damage inducible agent generates DNA damage in postmitotic HCs, but also suggest that DNA repair factors, like BRCA1, protect postmitotic HCs from DNA-damage induced cell death and hearing loss.Significance statement Sensorineural hearing loss is the most severe hearing loss caused by irreversible loss of cochlear hair cells. Hair cells are vulnerable to aging and ototoxic drug. Though DNA damage repair plays a critical role in protecting cells in many organs, it is poorly understood how DNA damage is repaired in hair cells. This study provides the first in vivo evidence demonstrating that cisplatin mainly induces DNA damage in outer hair cells and that BRCA1 promotes repair of DNA damage in outer hair cells and prevents outer hair cell loss as well as hearing loss.

USP11 deubiquitinates E-cadherin and maintains luminal fate of mammary tumor cells to suppress breast cancer.

Basal-like breast cancer may originate from luminal epithelial or cancerous cells. Inadequately repaired DNA damage impairs luminal differentiation and promotes aberrant luminal to basal trans-differentiation in mammary epithelial cells (MECs). Ubiquitin-specific peptidase 11 (USP11), a deubiquitinase, plays a critical role in DNA damage repair. The role of USP11 in controlling mammary cell differentiation and tumorigenesis remains poorly understood. We generated Usp11 knockout mice and breast cancer cell lines expressing wild-type (WT) and mutant form of USP11. By using these mutant mice, cell lines, and human USP11-deficient and -proficient breast cancer tissues, we tested how USP11 controls mammary cell fate. We generated Usp11 knock-out mice and found that deletion of Usp11 reduced the expression of E-cadherin and promoted DNA damage in MECs. Overexpression of WT USP11, but not a deubiquitinase-inactive mutant form of USP11, promoted luminal differentiation, enhanced DNA damage repair, and suppressed tumorigenesis in mice. Mechanistically, we found that USP11 enhanced the protein expression of E-cadherin dependent on its deubiquitinase activity, and that USP11 deubiquitinated E-cadherin at K738. We discovered that USP11 bound to E-cadherin through its C-terminal region. In human breast cancers, expression of USP11 was positively correlated with that of E-cadherin, and high USP11 predicted better recurrence-free survival. Our findings provide compelling genetic and biochemical evidence that USP11 not only promotes DNA damage repair but also deubiquitinates E-cadherin and maintains the luminal feature of mammary tumor cells, thereby suppressing luminal breast cancer.

TRanscranial AlterNating current stimulation FOR patients with mild Alzheimer's Disease (TRANSFORM-AD): a randomized controlled clinical trial.

BACKGROUND: The mechanistic effects of gamma transcranial alternating current stimulation (tACS) on hippocampal gamma oscillation activity in Alzheimer's Disease (AD) remains unclear. This study aimed to clarify beneficial effects of gamma tACS on cognitive functioning in AD and to elucidate effects on hippocampal gamma oscillation activity. METHODS: This is a double-blind, randomized controlled single-center trial. Participants with mild AD were randomized to tACS group or sham group, and underwent 30 one-hour sessions of either 40 Hz tACS or sham stimulation over consecutive 15 days. Cognitive functioning, structural magnetic resonance imaging (MRI), and simultaneous electroencephalography-functional MRI (EEG-fMRI) were evaluated at baseline, the end of the intervention and at 3-month follow-up from the randomization. RESULTS: A total of 46 patients were enrolled (23 in the tACS group, 23 in the sham group). There were no group differences in the change of the primary outcome, 11-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog) score after intervention (group*time, p = 0.449). For secondary outcomes, compared to the control group, the intervention group showed significant improvement in MMSE (group*time, p = 0.041) and MoCA scores (non-parametric test, p = 0.025), which were not sustained at 3-month follow-up. We found an enhancement of theta-gamma coupling in the hippocampus, which was positively correlated with improvements of MMSE score and delayed recall. Additionally, fMRI revealed increase of the local neural activity in the hippocampus. CONCLUSION: Effects on the enhancement of theta-gamma coupling and neural activity within the hippocampus suggest mechanistic models for potential therapeutic mechanisms of tACS. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03920826; Registration Date: 2019-04-19.

[Guidelines for traditional dietary care in autumn and winter].

The National Nutrition Plan(2017-2030) and the Healthy China Action Plan(2019-2030) propose to vigorously develop traditional dietary care services, fully leverage the role of traditional dietary care in modern nutrition, and guide citizens to develop dietary habits that are in line with the dietary characteristics of different regions in China. Traditional dietary care has a long history in China and is one of the brilliant treasures of Chinese cuisine and traditional Chinese medicine(TCM) culture. It has played an important role in disease prevention, treatment, and health preservation and longevity. To promote the traditional culture of TCM, and guide and standardize the application and promotion of dietary care, it is necessary to develop a dietary care guideline with TCM characteristics. Based on the theories and practices of TCM, the China Academy of Chinese Medical Sciences(CACMS) has developed this guideline, which is tailored to local conditions and combined with modern nutrition, and targets people with different physical constitutions. According to the principles of dialectical diet, tailored to people, times, and local conditions, reinforcing healthy qi, correction, the combination of meat and vegetables, and the combination of four qi and five flavors, suitable ingredients are recommended(including TCM materials that are both food and medicinal materials). By promoting the popularization and development of traditional dietary care, this guideline contributes to integrating the strength of TCM into a unique nutritional and health model with Chinese characteristics.

Safety and effectiveness of intraosseous regional prophylactic antibiotics in total knee arthroplasty: a systematic review and meta-analysis.

BACKGROUND: Intraosseous regional administration (IORA) as a widely applicable and clinically valuable route of administration has gained significant attention in the context of total knee arthroplasty (TKA) for the prophylactic administration of antibiotics. However, there is still controversy regarding its effectiveness and safety. The latest meta-analysis reports that the use of IORA for antibiotics in TKA is as safe and effective as IV administration in preventing prosthetic joint infection (PJI), but they did not separate the statistics for primary TKA and revision TKA, which may be inappropriate. There is currently a lack of evidence specifically comparing the outcomes of prophylactic antibiotic administration via IORA or IV route in primary/revision TKA, respectively, and new research evidence has emerged. PURPOSES: In this study, we conducted a systematic review and meta-analysis with the primary objective of comparing the local drug tissue concentration and the incidence of PJI between preoperative IORA and intravenous (IV) administration of prophylactic antibiotics in TKA. Additionally, the occurrence of complications between the two administration routes was also compared. PATIENTS AND METHODS: This meta-analysis was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement (PRISMA) guidelines. Retrospective cohort studies and prospective randomized controlled trials that utilized intraosseous local drug delivery for prophylactic antibiotics in knee arthroplasty were included. English literature from PubMed, Embase, and Cochrane Library databases was searched from the inception of each database until December 2023. Two researchers independently screened the literature, assessed the quality, and extracted data according to the inclusion criteria. The primary outcomes were local antibiotic tissue concentration and postoperative PJI incidence, while the secondary outcome was the occurrence of postoperative complications. Statistical analysis was performed using Review Manager 5.3 software. RESULTS: This study included 7 prospective randomized controlled trials and 5 retrospective cohort studies. A total of 4091 patients participated in the 12 included studies, with 1,801 cases receiving IORA and 2,290 cases in the control group. In terms of local drug tissue concentration, intraosseous infusion (IO) 500 mg vancomycin significantly increased the drug concentration in the periarticular adipose tissue (SMD: 1.36; 95% CI: 0.87-1.84; P < 0.001; I2 = 0%) and bone tissue (SMD: 0.94; 95% CI: 0.49-1.40; P < 0.001; I2 = 0%) compared to IV 1 g vancomycin. Regarding the incidence of postoperative PJI after primary TKA, IO 500 mg vancomycin was more effective in reducing the occurrence of PJI compared to IV 1 g vancomycin (OR: 0.19; 95% CI: 0.06-0.59; P < 0.001; I2 = 36%). Finally, no significant differences were found between the two groups in terms of postoperative pulmonary embolism (PE) (OR: 1.72; 95% CI: 0.22-13.69; P = 0.59; I2 = 0%) and vancomycin-related complications (OR: 0.54; 95% CI: 0.25-1.19; P = 0.44; I2 = 0%). CONCLUSIONS: Preoperative prophylactic antibiotic administration via IORA in TKA significantly increases local drug tissue concentration without significantly increasing systemic drug-related complications compared to traditional IV administration. In primary TKA, low-dose vancomycin via IORA is more effective in reducing the incidence of PJI compared to traditional IV regimens. However, its effectiveness remains controversial in high-risk populations for PJI, such as obese, diabetic, and renal insufficiency patients, as well as in revision TKA.

A spectrum of altered non-rapid eye movement sleep in schizophrenia.

Multiple facets of sleep neurophysiology, including electroencephalography (EEG) metrics such as non-rapid eye movement (NREM) spindles and slow oscillations, are altered in individuals with schizophrenia (SCZ). However, beyond group-level analyses, the extent to which NREM deficits vary among patients is unclear, as are their relationships to other sources of heterogeneity including clinical factors, ageing, cognitive profiles and medication regimens. Using newly collected high-density sleep EEG data on 103 individuals with SCZ and 68 controls, we first sought to replicate our previously reported group-level differences between patients and controls (original N=130) during N2 stage. Then in the combined sample (N=301 including 175 patients), we characterized patient-to-patient variability. We replicated all group-level mean differences and confirmed the high accuracy of our predictive model (AUC=0.93 for diagnosis). Compared to controls, patients showed significantly increased between-individual variability across many (26%) sleep metrics. Although multiple clinical and cognitive factors were associated with NREM metrics, collectively they did not account for much of the general increase in patient-to-patient variability. Medication regimen was a greater contributor to variability. Some sleep metrics including fast spindle density showed exaggerated age-related effects in SCZ, and patients exhibited older predicted biological ages based on the sleep EEG; further, among patients, certain medications exacerbated these effects, in particular olanzapine. Collectively, our results point to a spectrum of N2 sleep deficits among SCZ patients that can be measured objectively and at scale, with relevance to both the etiological heterogeneity of SCZ as well as potential iatrogenic effects of antipsychotic medication.

Efficacy and Safety of Pioglitazone/Metformin Fixed-Dose Combination Versus Uptitrated Metformin in Patients with Type 2 Diabetes without Adequate Glycemic Control: A Randomized Clinical Trial.

INTRODUCTION: We aim to evaluate the efficacy and safety of pioglitazone/metformin fixed-dose combination (FDC) versus uptitrated metformin in patients with type 2 diabetes mellitus (T2DM) without adequate glycemic control. METHODS: A total of 304 patients were recruited from 15 hospitals in China and randomly assigned (1:1) to the test group (pioglitazone/metformin FDC, 15/500 mg) or the control group (uptitrated metformin, 2000-2500 mg/day). The primary endpoint was the proportion of patients with glycated hemoglobin A1c (HbA1c) ≤ 6.5% and ≤ 7.0% at week 16. The secondary outcomes included the change from baseline in glucose, serum lipids, and liver function. Full analysis set (FAS) and per-protocol set (PPS) were used for analyses. RESULTS: In the test group, 103 (69.59%) patients reached HbA1c ≤ 7.0% (FAS, P = 0.009), with 68 (45.95%) patients achieved HbA1c ≤ 6.5 (FAS, P = 0.043). More reduction in HbA1c, homeostatic model assessment for insulin resistance, and diastolic pressure was found. Bodyweight, body mass index, and high-density lipoprotein cholesterol increased markedly. The changes of triglycerides, alanine transaminase, aspartate aminotransferase, and high-sensitivity C-reactive protein decreased noticeably. There were no significant differences in rates of adverse events between the two groups. CONCLUSIONS: Pioglitazone/metformin FDC was superior to uptitrated metformin among patients with T2DM without adequate glycemic control. TRIAL REGISTRATION NUMBER: This trial is registered with the Chinese Clinical Trial Registry (ChiCTR1900028606).

Evolution of a Eukaryotic Transcription Factor's co-TF Dependence Involves Multiple Intrinsically Disordered Regions Affecting Activation and Autoinhibition.

Combinatorial control by multiple transcription factors (TFs) is a hallmark of eukaryotic gene regulation. Despite its prevalence and crucial roles in enhancing specificity and integrating information, the mechanisms behind why eukaryotic TFs depend on one another, and whether such interdependence evolves, are not well understood. We exploit natural variation in co-TF dependence in the yeast phosphate starvation (PHO) response to address this question. In the model yeast Saccharomyces cerevisiae, the main TF, Pho4, relies on the co-TF Pho2 to regulate ~28 genes. In a related yeast pathogen, Candida glabrata, its Pho4 exhibits significantly reduced Pho2 dependence and has an expanded target set of ~70 genes. Biochemical analyses showed C. glabrata Pho4 (CgPho4) binds to the same consensus motif with 3-4-fold higher affinity than ScPho4 does. A machine-learning-based prediction and yeast one-hybrid assay identified two Intrinsically Disordered Regions (IDRs) in CgPho4 that boost the activity of the main activation domain but showed little to no activity on their own. We also found evidence for autoinhibition behind the co-TF dependence in ScPho4. An IDR in ScPho4 next to its DNA binding domain was found to act as a double-edged sword: it both allows for enhanced activity with Pho2, and inhibits Pho4's activity without Pho2. This study provides a detailed molecular picture of how co-TF dependence is mediated and how its evolution, mainly driven by IDR divergence, can lead to significant rewiring of the regulatory network.

Fluspirilene exerts an anti-glioblastoma effect through suppression of the FOXM1-KIF20A axis.

Given the infiltrative nature of human glioblastoma (GBM), cocktail drug therapy will remain a vital tool for the treatment of the disease. We investigated fluspirilene, perphenazine, and sulpiride, three classic anti-schizophrenic drugs, as possible anti-GBM agents. The CCK-8 assay demonstrated that fluspirilene possesses the most outstanding anti-GBM effect. We performed molecular mechanisms studies in vitro and an orthotopic xenograft model in mice. Fluspirilene inhibited proliferation and migration in vitro in U87MG and U251 GBM cell lines. Flow cytometry demonstrated that treatment increased apoptosis and cells accumulated in the G2/M phase. Our analysis of publicly available expression data for several cell lines treated with the drug led to the identification of several genes, including KIF20A, that are downregulated by fluspirilene and lead to growth inhibition/apoptosis. We also demonstrated that siRNA knockdown of KIF20A, a member of the kinesin family, attenuated cell proliferation in GBM cells and an orthotopic xenograft model in mice. A regulator of KIF20A, the oncogenic transcription factor FOXM1, was identified using the String database, which harbors protein interaction networks. In fluspirilene-treated cells, FOXM1 protein was decreased, indicating that KIF20A was downregulated in the presence of the drug due to decreased FOXM1 protein. These results demonstrate that fluspirilene is an effective anti-GBM agent that works by suppressing the FOXM1-KIF20A oncogenic axis.

Effectiveness of non-pharmaceutical interventions for COVID-19 in USA.

Worldwide, governments imposed non-pharmaceutical interventions (NPIs) during the COVID-19 pandemic to contain the pandemic more effectively. We examined the effectiveness of individual NPIs in the United States during the first wave of the pandemic. Three types of analyses were performed. First, a prototypical Bayesian hierarchical model was employed to gauge the effectiveness of five NPIs and they are gathering restriction, restaurant capacity restriction, business closure, school closure, and stay-at-home order in the 42 states with over 100 deaths by the end of the wave. Second, we examined the effectiveness of the face mask mandate, the sixth and most controversial NPI by counterfactual modeling, which is a variant of the prototypical Bayesian hierarchical model allowing us to answer the question of what if the state had imposed the mandate or not. The third analysis used an advanced Bayesian hierarchical model to evaluate the effectiveness of all six NPIs in all 50 states and the District of Columbia, and thereby provide a full-scale estimation of the effectiveness of NPIs and the relative effectiveness of each NPI in the entire United States. Our results have enhanced the collective knowledge on the general effectiveness of NPIs in arresting the spread of COVID-19.

Combined analysis of cecal microbiota and metabolomics reveals the intervention mechanism of Dayuan Yin in acute lung injury.

The ancient Chinese medicinal formula, Dayuan Yin (DYY), has a long history of use in treating respiratory ailments and is shown to be effective in treating acute infectious diseases. This study aims to explore how DYY may impact intestinal flora and metabolites induced by acute lung injury (ALI). ALI rats were induced with lipopolysaccharide (LPS) to serve as models for assessing the anti-ALI efficacy of DYY through multiple lung injury indices. Changes in intestinal microflora were assessed via 16SrRNA gene sequencing, while cecum contents were analyzed using non-targeted metabonomics. Differential metabolites were identified through data analysis, and correlations between metabolites, microbiota, and inflammatory markers were examined using Pearson's correlation analysis. DYY demonstrated a significant improvement in LPS-induced lung injury and altered the composition of intestinal microorganisms, and especially reduced the potential harmful bacteria and enriched the beneficial bacteria. At the gate level, DYY exhibited a significant impact on the abundance of Bacteroidota and Firmicutes in ALI rats, as well as on the regulation of genera such as Ruminococcus, Lactobacillus, and Romboutsia. Additionally, cecal metabonomics analysis revealed that DYY effectively modulated the abnormal expression of 12 key metabolic biomarkers in ALI rats, thereby promoting intestinal homeostasis through pathways such as purine metabolism. Furthermore, Pearson's analysis indicated a strong correlation between the dysregulation of intestinal microbiota, differential metabolites, and inflammation. These findings preliminarily confirm that ALI is closely related to cecal microbial and metabolic disorders, and DYY can play a protective role by regulating this imbalance, which provides a new understanding of the multi-system linkage mechanism of DYY improving ALI.

Glucoraphanin and sulforaphane mitigate TNFα-induced Caco-2 monolayers permeabilization and inflammation.

Intestinal permeabilization is central to the pathophysiology of chronic gut inflammation. This study investigated the efficacy of glucoraphanin (GR), prevalent in cruciferous vegetables, particularly broccoli, and its derivative sulforaphane (SF), in inhibiting tumor necrosis factor alpha (TNFα)-induced Caco-2 cell monolayers inflammation and permeabilization through the regulation of redox-sensitive events. TNFα binding to its receptor led to a rapid increase in oxidant production and subsequent elevation in the mRNA levels of NOX1, NOX4, and Duox2. GR and SF dose-dependently mitigated both these short- and long-term alterations in redox homeostasis. Downstream, GR and SF inhibited the activation of the redox-sensitive signaling cascades NF-κB (p65 and IKK) and MAPK ERK1/2, which contribute to inflammation and barrier permeabilization. GR (1 µM) and SF (0.5-1 µM) prevented TNFα-induced monolayer permeabilization and the associated reduction in the levels of the tight junction (TJ) proteins occludin and ZO-1. Both GR and SF also mitigated TNFα-induced increased mRNA levels of the myosin light chain kinase, which promotes TJ opening. Molecular docking suggests that although GR is mostly not absorbed, it could interact with extracellular and membrane sites in NOX1. Inhibition of NOX1 activity by GR would mitigate TNFα receptor downstream signaling and associated events. These findings support the concept that not only SF, but also GR, could exert systemic health benefits by protecting the intestinal barrier against inflammation-induced permeabilization, in part by regulating redox-sensitive pathways. GR has heretofore not been viewed as a biologically active molecule, but rather, the benign precursor of highly active SF. The consumption of GR and/or SF-rich vegetables or supplements in the diet may offer a means to mitigate the detrimental consequences of intestinal permeabilization, not only in disease states but also in conditions characterized by chronic inflammation of dietary and lifestyle origin.

Tree Rings Mercury Controlled by Atmospheric Gaseous Elemental Mercury and Tree Physiology.

Tree rings are an emerging atmospheric mercury (Hg) archive. Questions have arisen, though, regarding their mechanistic controls and reliability. Here, we report contrasting tree-ring Hg records in three collocated conifer species: Norway spruce (Picea abies), Scots pine (Pinus sylvestris), and European larch (Larix decidua), which are from a remote boreal forest. Centennial atmospheric Hg trends at the site, derived from varved lake sediments, peats, and atmospheric monitoring, indicated a steady rise from the 1800s, peaking in the 1970s, and then declining. Prior to ca. 2005, larch and spruce tree rings reproduced the peak in the atmospheric Hg trend, while pine tree rings peaked in the 1930s, likely due to the prolonged sapwood period and ambiguity in the heartwood-sapwood boundary of pine. Since ca. 2005, tree rings from all species showed increasing Hg concentrations in the physiologically active outer rings despite declining atmospheric Hg concentrations. The good agreement between Hg and nitrogen concentrations in active tree-ring cells indicates a similar transport mechanism and cautions against their applicability as atmospheric Hg archives. Our results suggest that tree-ring Hg records are controlled by atmospheric Hg and tree physiology. We provide recommendations for using tree-ring Hg archives that take tree physiology into account.

Study on the mechanism of ROS-induced oxidative stress injury and the broad-spectrum antimicrobial performance of nickel ion-doped V6O13 powder.

In this study, pure V6O13 and nickel ion-doped V6O13 powders were synthesized by a simple hydrothermal-calcination method, and their broad-spectrum antimicrobial properties and mechanisms were investigated. The crystal structure, morphology, and chemical state of the powders were thoroughly analyzed by XRD, SEM, TEM, XPS, and UV-Vis. Their antimicrobial properties and mechanisms were evaluated by the ring of inhibition, bio-SEM, live-dead cell staining, ROS detection, and protein leakage experiments. The results showed that nickel ion doping modulated the oxygen defects of V6O13, generating more reactive oxygen species and leading to more severe oxidative stress, resulting in a broad-spectrum and highly efficient antimicrobial effect. This study also revealed the antimicrobial mechanism based on oxygen defect -induced ROS production, which caused cellular oxidative stress damage, leading to leakage of intracellular substances and cell death. This study not only demonstrates the potential of V6O13 as an efficient antimicrobial agent but also provides a strong experimental basis and theoretical support for the engineering design and optimization of novel antimicrobial materials by modulating material defects through ion doping.

Curcumol effectively improves obesity through GDF15 induction via activation of endoplasmic reticulum stress response.

The escalating prevalence of obesity presents a formidable global health challenge, underscoring the imperative for efficacious pharmacotherapeutic interventions. However, current anti-obesity medications often exhibit limited efficacy and adverse effects, necessitating the exploration of alternative therapeutic approaches. Growth differentiation factor 15 (GDF15) has emerged as a promising target for obesity management, given its crucial role in appetite control and metabolic regulation. In this study, we aimed to investigate the efficacy of curcumol, a sesquiterpene compound derived from plants of the Zingiberaceae family, in obesity treatment. Our findings demonstrate that curcumol effectively induces the expression of GDF15 through the activation of the endoplasmic reticulum stress pathway. To confirm the role of GDF15 as a critical target for curcumol's function, we compared the effects of curcumol in wild-type mice and Gdf15-knockout mice. Using a high-fat diet-induced obese murine model, we observed that curcumol led to reduced appetite and altered dietary preferences mediated by GDF15. Furthermore, chronic curcumol intervention resulted in promising anti-obesity effects. Additionally, curcumol administration improved glucose tolerance and lipid metabolism in the obese mice. These findings highlight the potential of curcumol as a GDF15 inducer and suggest innovative strategies for managing obesity and its associated metabolic disorders. In conclusion, our study provides evidence for the efficacy of curcumol in obesity treatment by inducing GDF15 expression. The identified effects of curcumol on appetite regulation, dietary preferences, glucose tolerance, and lipid metabolism emphasize its potential as a therapeutic agent for combating obesity and related metabolic disorders.