PlantPAD: a platform for large-scale image phenomics analysis of disease in plant science.

Plant disease, a huge burden, can cause yield loss of up to 100% and thus reduce food security. Actually, smart diagnosing diseases with plant phenomics is crucial for recovering the most yield loss, which usually requires sufficient image information. Hence, phenomics is being pursued as an independent discipline to enable the development of high-throughput phenotyping for plant disease. However, we often face challenges in sharing large-scale image data due to incompatibilities in formats and descriptions provided by different communities, limiting multidisciplinary research exploration. To this end, we build a Plant Phenomics Analysis of Disease (PlantPAD) platform with large-scale information on disease. Our platform contains 421 314 images, 63 crops and 310 diseases. Compared to other databases, PlantPAD has extensive, well-annotated image data and in-depth disease information, and offers pre-trained deep-learning models for accurate plant disease diagnosis. PlantPAD supports various valuable applications across multiple disciplines, including intelligent disease diagnosis, disease education and efficient disease detection and control. Through three applications of PlantPAD, we show the easy-to-use and convenient functions. PlantPAD is mainly oriented towards biologists, computer scientists, plant pathologists, farm managers and pesticide scientists, which may easily explore multidisciplinary research to fight against plant diseases. PlantPAD is freely available at http://plantpad.samlab.cn.

Oxide Ion-Conducting Materials Containing Tetrahedral Moieties: Structures and Conduction Mechanisms.

This Review presents an overview from the perspective of tetrahedral chemistry on various oxide ion-conducting materials containing tetrahedral moieties which have received continuous growing attention as candidates for key components of various devices, including solid oxide fuel cells and oxygen sensors, due to the deformation and rotation flexibility of tetrahedral units facilitating oxide ion transport. Emphasis is placed on the structural and mechanistic features of various systems ranging from crystalline to amorphous materials, which include a variety of gallates, silicates, germanates, molybdates, tungstates, vanadates, aluminates, niobate, titanates, indium oxides, and the newly reported borates. They contain tetrahedral units in either isolated or linked manners forming different polyhedral dimensionality (0 to 3) with various defect properties and transport mechanisms. The development of oxide ion conductors containing tetrahedral moieties and the elucidation of the roles of tetrahedral units in oxide ion migration have demonstrated diverse opportunities for discovering superior electrolytes for solid oxide fuel cells and other related devices and provided useful clues for uncovering the key factors directing fast oxide ion conduction.

A Poly(amino acid)-Based Nanomedicine Strategy: Telomere-Telomerase Axis Targeting and Magnetic Resonance Imaging in Hepatocellular Carcinoma Treatment.

Targeting telomere maintenance has emerged as a promising strategy for hepatocellular carcinoma (HCC) treatment. However, given the duality of the telomere-telomerase axis in telomere maintenance, a comprehensive strategy is urgently needed. Herein, we develop a poly(amino acid) (D-PAAs)-based strategy for spatiotemporal codelivery of telomerase inhibitor, BIBR1523, and AKT inhibitor, isobavachalcone. By leveraging D-PAAs' modifiability, we synthesize polymer-inhibitor conjugates (PB and PI) and a folic acid-decorated tumor-targeting vector (PF). These building blocks undergo micellization to fabricate a codelivery nanomedicine (P-BI@P-FA) by exploiting D-PAAs' noncovalent assembly. P-BI@P-FA improves the pharmacokinetics, tumor selectivity, and bioavailability of small molecule inhibitors and initiates a dual telomere-specific inhibition by combining telomerase deactivation with telomere disruption. Furthermore, a hybrid tumor-targeting magnetic nanosystem is designed using D-PAAs and manganese dioxide to showcase magnetic resonance imaging capacities. Our D-PAAs-based strategy addresses the pressing need for telomere-specific HCC treatment while allowing for diagnostic application, presenting a promising avenue for nanomedicine design.

Trans-Cinnamaldehyde Inhibition of Pyruvate Dehydrogenase: Effects on Streptococcus mutans Carbohydrate Metabolism.

Dental caries is a chronic oral infectious disease, and Streptococcus mutans (S. mutans) plays an important role in the formation of dental caries. Trans-cinnamaldehyde (CA) exhibits broad-spectrum antibacterial activity; however, its target and mechanism of action of CA on S. mutans needs to be further explored. In this study, it was verified that CA could inhibit the growth and biofilm formation of S. mutans. Further proteomic analysis identified 33, 55, and 78 differentially expressed proteins (DEPs) in S. mutans treated with CA for 1, 2, and 4 h, respectively. Bioinformatics analysis showed that CA interfered with carbohydrate metabolism, glycolysis, pyruvate metabolism, and the TCA cycle, as well as amino acid metabolism of S. mutans. Protein interactions suggested that pyruvate dehydrogenase (PDH) plays an important role in the antibacterial effect of CA. Moreover, the upstream and downstream pathways related to PDH were verified by various assays, and the results proved that CA not only suppressed the glucose and sucrose consumption and inhibited glucosyltransferase (GTF) and lactate dehydrogenase (LDH) activities but also decreased the ATP production. Interestingly, the protein interaction, qRT-PCR, and molecular docking analysis showed that PDH might be the target of CA to fight S. mutans. In summary, the study shows that CA interferes with the carbohydrate metabolism of bacteria by inhibiting glycolysis and the tricarboxylic acid (TCA) cycle via binding to PDH, which verifies that PDH is a potential target for the development of new drugs against S. mutans.

Safety, tolerability, and pharmacokinetics of HRS9432(A) injection in healthy Chinese subjects: a phase-I randomized, double-blind, dose escalation, placebo-controlled study.

HRS9432(A) is a long-acting echinocandin antifungal medication primarily used to treat invasive fungal infections, particularly invasive candidiasis. The safety, tolerability, and pharmacokinetic characteristics of HRS9432(A) injection were investigated in a randomized, double-blind, placebo-controlled, single- and multiple-ascending-dose Phase I study involving 56 healthy adult subjects. Doses ranging from 200 to 1200 mg were administered. Safety was continually monitored, including adverse events, clinical laboratory examinations, vital signs, 12-lead electrocardiograms, and physical examinations, while the pharmacokinetic profile within the body was evaluated. The results indicated that concentrations of HRS9432 peaked immediately after infusion, demonstrating essentially linear pharmacokinetic characteristics within the dosage range of 200-1,200 mg. It exhibited a low clearance rate and an extended half-life, with a clearance of approximately 0.2 L/h, a volume of distribution of around 40 L, and a half-life of approximately 140h following a single dose. The accumulation index for AUC0-τ after multiple doses ranged from 1.41 to 1.75. No severe adverse events occurred during the study, and the severity of all adverse events was mild or moderate. Therefore, the intravenous administration of HRS9432(A) in healthy Chinese adult subjects, either as multiple infusions of 200 to 600 mg (once a week, four doses) or as a single infusion of 900-1,200 mg, demonstrated overall good safety and tolerability. The pharmacokinetic exhibited essentially linear characteristics in the body, supporting a weekly dosing frequency for clinical applications and providing additional options for the treatment or prevention of invasive fungal infections. CLINICAL TRIALS: This study is registered with the International Clinical Trials Registry Platform as ChiCTR2300073525.

Linking watershed formation with the phylogenetic distribution of a soil microscopic fungus in Yunnan Province, China.

BACKGROUND: Phylogeographic studies have gained prominence in linking past geological events to the distribution patterns of biodiversity, primarily in mountainous regions. However, such studies often focus on plant taxa, neglecting the intricate biogeographical patterns of microbes, particularly soil microbial communities. This article explores the spatial distribution of the nematode-trapping fungus Arthrobotrys oligospora, a widespread microorganism, in a tectonically active region at the southeastern edge of the Qinghai-Tibetan Plateau. By analysing the genetic variation of this fungus alongside the historical structure of major river watersheds, we sought to uncover potential connections between the two. Our study involved sampling 149 strains from 116 sites across six major watersheds in the region. RESULTS: The resulting haplotype network revealed five distinct clusters, each corresponding closely to a specific watershed. These clusters exhibited high haplotype diversity and low nucleotide diversity, supporting the notion of watershed-based segregation. Further analysis of haplotypes shared across watersheds provided evidence for three proposed past river connections. In particular, we found numerous shared haplotypes between the Yangtze and Mekong basins, as well as between the Yangtze and the Red basins. Evidence for a Irrawaddy-Salween-Red and a Yangtze-Pearl-Red river connections were also portrayed in our mapping exercise. CONCLUSIONS: These findings emphasize the crucial role of historical geomorphological events in shaping the biogeography of microbial biodiversity, alongside contemporary biotic and abiotic factors. Watershed perimeters emerged as effective predictors of such patterns, suggesting their suitability as analytical units for regional-scale studies. Our study also demonstrates the potential of microorganisms and phylogeographic approaches to complement traditional geological analyses, providing a more comprehensive understanding of past landscape structure and its evolution.

Sodium thiosulfate: A donor or carrier signaling molecule for hydrogen sulfide?

Sodium thiosulfate has been used for decades in the treatment of calciphylaxis and cyanide detoxification, and has recently shown initial therapeutic promise in critical diseases such as neuronal ischemia, diabetes mellitus, heart failure and acute lung injury. However, the precise mechanism of sodium thiosulfate remains incompletely defined and sometimes contradictory. Although sodium thiosulfate has been widely accepted as a donor of hydrogen sulfide (H2S), emerging findings suggest that it is the executive signaling molecule for H2S and that its effects may not be dependent on H2S. This article presents an overview of the current understanding of sodium thiosulfate, including its synthesis, biological characteristics, and clinical applications of sodium thiosulfate, as well as the underlying mechanisms in vivo. We also discussed the interplay of sodium thiosulfate and H2S. Our review highlights sodium thiosulfate as a key player in sulfide signaling with the broad clinical potential for the future.

99mTc-HFAPi SPECT imaging predicts left ventricular remodeling after acute myocardial infarction.

BACKGROUND: Despite improved treatments for acute myocardial infarction (AMI), myocardial fibrosis remains a key driver of adverse left ventricular (LV) remodeling and increased mortality. Fibroblast activation and proliferation significantly contribute to this process by enhancing cardiac fibrosis, which can lead to detrimental changes in LV structure. This study evaluates the effectiveness of 99mTc-labeled fibroblast activation protein inhibitor (99mTc-HFAPi) SPECT imaging in predicting LV remodeling over 12 months in post-AMI patients. METHODS: A cohort of 58 AMI patients (46 males, median age 61 [53, 67] years) underwent baseline 99mTc-HFAPi imaging (5 ± 2 days post-MI), perfusion imaging (6 ± 2 days post-MI), and echocardiography (2 ± 2 days post-MI). Additionally, 15 patients had follow-up 99mTc-HFAPi and perfusion imaging, while 30 patients had follow-up echocardiography. Myocardial 99mTc-HFAPi activity was assessed at the patient level. LV remodeling was defined as a ≥10% increase in LV end-diastolic diameter (LVEDD) or LV end-systolic diameter (LVESD) from baseline to follow-up echocardiography. RESULTS: AMI patients displayed localized but non-uniform 99mTc-HFAPi uptake, exceeding perfusion defects. Baseline 99mTc-HFAPi activity exhibited significant correlations with BNPmax, LDHmax, cTNImax, and WBCmax, inversely correlating with LVEF. After 12 months, 11 patients (36.66%) experienced LV remodeling. Univariate regression analysis demonstrated an association between baseline 99mTc-HFAPi uptake extent and LV remodeling (OR = 2.14, 95%CI, 1.04, 4.39, P = 0.038). CONCLUSIONS: 99mTc-HFAPi SPECT imaging holds promise in predicting LV remodeling post-MI, providing valuable insights for patient management and prognosis.

Safety and adherence of bictegravir/emtricitabine/tenofovir alafenamide for HIV post-exposure prophylaxis among adults in Guiyang China: a prospective cohort study.

BACKGROUND: The effectiveness of post-exposure prophylaxis (PEP) depends on participants adherence, making it crucial to assess and compare regimen options to enhance human immunodeficiency virus (HIV) prophylaxis strategies. However, no prospective study in China has shown that the completion rate and adherence of single-tablet regimens in HIV PEP are higher than those of multi-tablet preparations. Therefore, this study aimed to assess the completion rate and adherence of two HIV PEP regimens. METHODS: In this single-center, prospective, open-label cohort study, we included 179 participants from May 2022 to March 2023 and analyzed the differences in the 28-day medication completion rate, adherence, safety, tolerance, and effectiveness of bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) and tenofovir disoproxil fumarate, emtricitabine, and dolutegravir (TDF/FTC + DTG). RESULTS: The PEP completion rate and adherence were higher in the BIC/FTC/TAF group than in the TDF/FTC + DTG group (completion rate: 97.8% vs. 82.6%, P = 0.009; adherence: 99.6 ± 2.82% vs. 90.2 ± 25.29%, P = 0.003). The incidence of adverse reactions in the BIC/FTC/TAF and TDF/FTC + DTG groups was 15.2% and 10.3% (P = 0.33), respectively. In the TDF/FTC + DTG group, one participant stopped PEP owing to adverse reactions (1.1%). No other participants stopped PEP due to adverse events. CONCLUSIONS: BIC/FTC/TAF and TDF/FTC + DTG have good safety and tolerance as PEP regimens. BIC/FTC/TAF has a higher completion rate and increased adherence, thus, is recommended as a PEP regimen. These findings emphasize the importance of regimen choice in optimizing PEP outcomes. TRIAL REGISTRATION: The study was registered in the Chinese Clinical Trial Registry (registration number: ChiCTR2200059994(2022-05-14), https://www.chictr.org.cn/bin/project/edit?pid=167391 ).

Temporal dynamics of the microbial heterogeneity-diversity relationship in microcosmic systems.

Spatial heterogeneity significantly enhances biodiversity, representing one of the ecology's most enduring paradigms. However, many studies have found decreasing, humped, and neutral correlations between spatial heterogeneity and biodiversity (heterogeneity-diversity relationships, HDR). These findings have pushed this widely accepted theory back into controversy. Microbial HDR research has lagged compared to that of plants and animals. Nevertheless, microbes have features that add a temporal-scale perspective to HDR research that is critical to understanding patterns of HDR. In this study, 157 microcosms with different types spatial heterogeneity were set up to map the HDR of microorganisms and their temporal dynamics using high-throughput sequencing techniques. The results show that the following: 1. Spatial heterogeneity can significantly alter microbial diversity in microcosmic systems. Changes in microbial diversity, in turn, lead to changes in environmental conditions. These changes caused microorganisms to exhibit increasing, decreasing, humped, U-shaped, and neutral HDR patterns. 2. The emergence of HDR patterns is characterized by temporal dynamics. Additionally, the HDR patterns generated by spatial structural and compositional heterogeneity exhibit inconsistent emergence times. These results suggest that the temporal dynamics of HDR may be one of the reasons for the coexistence of multiple patterns in previous studies. The feedback regulation between spatial heterogeneity-biodiversity-environmental conditions is an essential reason for the temporally dynamics of HDR patterns. All future ecological studies should pay attention to the temporal dynamic patterns of ecological factors.

Recent advances in pyruvate dehydrogenase kinase inhibitors: Structures, inhibitory mechanisms and biological activities.

Metabolism is reprogrammed in a variety of cancer cells to ensure their rapid proliferation. Cancer cells prefer to utilize glycolysis to produce energy as well as to provide large amounts of precursors for their division. In this process, cancer cells inhibit the activity of pyruvate dehydrogenase complex (PDC) by upregulating the expression of pyruvate dehydrogenase kinases (PDKs). Inhibiting the activity of PDKs in cancer cells can effectively block this metabolic transition in cancer cells, while also activating mitochondrial oxidative metabolism and promoting apoptosis of cancer cells. To this day, the study of PDKs inhibitors has become one of the research hotspots in the field of medicinal chemistry. Novel structures targeting PDKs are constantly being discovered, and some inhibitors have entered the clinical research stage. Here, we reviewed the research progress of PDKs inhibitors in recent years and classified them according to the PDKs binding sites they acted on, aiming to summarize the structural characteristics of inhibitors acting on different binding sites and explore their clinical application value. Finally, the shortcomings of some PDKs inhibitors and the further development direction of PDKs inhibitors are discussed.

Small-molecule modulators of tumor immune microenvironment.

In recent years, tumor immunotherapy, aimed at increasing the activity of immune cells and reducing immunosuppressive effects, has attracted wide attention. Among them, immune checkpoint blocking (ICB) is the most commonly explored therapeutic approach. All approved immune checkpoint inhibitors (ICIs) are clinically effective monoclonal antibodies (mAbs). Compared with biological agents, small-molecule drugs have many unique advantages in tumor immunotherapy. Therefore, they also play an important role. Immunosuppressive signals such as PD-L1, IDO1, and TGF-ß, etc. overexpressed in tumor cells form the tumor immunosuppressive microenvironment. In addition, the efficacy of multi-pathway combined immunotherapy has also been reported and verified. Here, we mainly reviewed the mechanism of tumor immunotherapy, analyzed the research status of small-molecule modulators, and discussed drug candidates' structure-activity relationship (SAR). It provides more opportunities for further research to design more immune small-molecule modulators with novel structures.

A latent class analysis of family resilience and its relationship with fear of recurrence in lung cancer patients: a cross-sectional study.

PURPOSE: Family resilience helps cancer-affected families overcome challenges and may influence an individual's fear of cancer recurrence (FCR). Identifying distinct classes of family resilience among lung cancer patients is crucial for tailored interventions. This study aimed to identify latent classes of family resilience in lung cancer patients and explore their relationships with FCR. METHODS: Three hundred ten lung cancer patients from three hospitals in Fujian were recruited from June to September 2021. Clinical data were extracted from medical records, while sociodemographic details, family resilience, and FCR were self-reported. A latent class analysis was performed to identify family resilience classes. RESULTS: A 4-class solution showed the best fit. Compared to Class 1, the patients who had no comorbidities (ORs = 3.480-16.005) had an increased likelihood of belonging to Class 2 and 3, while those who were not family breadwinners (ORs = 0.118-0.176) had a decreased likelihood. Further, the patients who (1) did not lack interest/pleasure in doing things during the past 2-week period (OR = 7.057), (2) were never smokers (OR = 6.230), and (3) were urban residents (OR = 8.985) had an increased likelihood of belonging to Class 4, while those who were (1) male (OR = 0.167), (2) not the family breadwinner (OR = 0.152), and (3) had none or only one child (OR = 0.203) had a decreased likelihood of belonging to Class 4. The FCR level differed significantly among these four classes. CONCLUSION: Our study identified four distinct classes of family resilience among Chinese lung cancer patients. FCR severity decreased with increasing levels of family resilience.

PHLPP1 inhibits the growth and aerobic glycolysis activity of human ovarian granular cells through inactivating AKT pathway.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a disorder characterized by hyperandrogenism, ovulatory dysfunction, and polycystic ovarian morphologic features, and PCOS is associated with infertility. PH domain Leucine-rich repeat Protein Phosphatase 1 (PHLPP1) has been shown to regulate AKT. The aim of present study is to investigate the role of PHLPP1 in PCOS. METHODS: The expression levels of PHLPP1 in dihydrotestosterone (DHT)-treated human ovarian granular KGN cells were determined by qRT-PCR and Western blot. PHLPP1 was silenced or overexpressed using lentivirus. Cell proliferation was detected by CCK-8. Apoptosis and ROS generation were analyzed by flow cytometry. Glycolysis was analyzed by measuring extracellular acidification rate (ECAR). RESULTS: DHT treatment suppressed proliferation, promoted apoptosis, enhanced ROS, and inhibited glycolysis in KGN cells. PHLPP1 silencing alleviated the DHT-induced suppression of proliferation and glycolysis, and promotion of apoptosis and ROS in KGN cells. PHLPP1 regulated cell proliferation and glycolysis in human KGN cells via the AKT signaling pathway. CONCLUSIONS: Our results showed that PHLPP1 mediates the proliferation and aerobic glycolysis activity of human ovarian granular cells through regulating AKT signaling.

Identification and Nursing Care of a Stroke Patient with Internal Iliac Artery Branch Rupture and Bleeding.

To summarize the experience of identifying and caring for a stroke patient with ruptured internal iliac artery branch bleeding. The experience was summarized in 3 aspects, including how to recognize the presence of active bleeding in the patient, confirmation of the diagnosis and treatment of the bleeding point, prevention of postoperative complications, and rehabilitation care. After aggressive treatment and care, the patient was discharged after 30 days of hospitalization and improved.

Fear of recurrence in postoperative lung cancer patients: Trajectories, influencing factors and impacts on quality of life.

AIMS: To investigate the trajectory, influencing factors and dynamic relationships between fear of cancer recurrence (FCR) and quality of life (QOL) in lung cancer patients. DESIGN: Prospective longitudinal study. METHODS: Longitudinal data from 310 lung cancer patients across three hospitals in China were assessed at 1, 3, 6 and 12 months postoperatively (T1 -T4 ). Descriptive statistics characterised patient demographics, clinical characteristics, levels of FCR and QOL. A linear mixed-effects model was employed to analyse FCR trajectories, identify influencing factors on these trajectories, and predict the impact of FCR on QOL. RESULTS: FCR changed significantly over time, with a slight decrease during T1 -T2 , an increase at T3 and gradual decline at T4 . Higher fear levels were associated with female sex, suburban or rural residency, being a family breadwinner, presence of comorbidities and negative coping behaviours, and low family resilience. QOL negatively correlated with FCR, and FCR predicted lower QOL. CONCLUSIONS: At 3 and 6 months postoperatively, lung cancer patients, especially women, suburban or rural residents, family breadwinners, those with comorbidities, negative coping behaviours and low family resilience, reported high levels of FCR. Healthcare providers should pay special attention to lung cancer patients especially during the period of 3-6 months post-surgery and offer tailored interventions to improve their QOL. IMPLICATIONS FOR THE PROFESSION AND PATIENT CARE: Understanding the FCR trajectories, its influencing factors and its negative impacts on QOL can guide the development of targeted interventions to reduce fear and enhance well-being in patients with cancer. IMPACT: Identifying the trajectories and influencing factors of fear of lung cancer recurrence in patients at different time points informs future research on targeted interventions to improve QOL. REPORTING METHOD: The study adhered to the guidelines outlined in the Statement on Reporting Observational Longitudinal Research.

Secondary metabolites from the fungus Cladosporium xylophilum.

A new cladosporol derivative xylophilum A (1), together with 10 known compounds (2-11), were isolated from the rice fermentation of the fungus Cladosporium xylophilum. Their structures were established by extensive spectroscopic methods and comparison of their NMR data with literatures. The antimicrobial activity of compound 1 against 11 kinds of pathogenic microbial was evaluated, but no significant activity was found (MIC >100 µg/ml).

Human papillomavirus vaccination: a quantitative cross-sectional study of perceived barriers, influential advisors, and acculturation among Chinese college students aged 18-26 in the USA.

HPV vaccines are highly effective in preventing HPV-associated cancers; however, HPV vaccination uptake is low among Chinese students studying at U.S. colleges. The purposes of this study were to evaluate (a) perceived barriers and influential others trusted for advice regarding HPV vaccination and (b) factors (i.e. HPV vaccination, acculturation) related to barriers and influential advisors among 18- to 26-year-old Chinese students attending U.S. colleges. We used a cross-sectional design to obtain self-reported data in 2019 from a chain-referral sample of 213 Chinese students. Among 125 respondents who were unvaccinated or partially vaccinated, the reported barriers to receiving the HPV vaccine included: (a) lack of recommendations from a healthcare provider, (b) lack of risk perception for HPV infection, and (c) limited knowledge about HPV vaccination locations. The influential advisors for receiving HPV vaccination were doctors, parents, self, nurses, and same-sex friends. Multivariate analysis revealed that unvaccinated respondents were more likely to report the following barriers to HPV vaccination: (a) lack of recommendations from a healthcare provider, (b) lack of risk perception for HPV infection, (c) limited knowledge about vaccination locations, and (d) uncertainty about effectiveness. High Asian identified respondents were more likely to perceive barriers related to limited knowledge about vaccination locations and uncertainty about effectiveness, while they were less likely to state nurses as influential advisors. Individuals who received one or more HPV vaccine doses were more inclined to view same-sex friends and nurses as influential advisors for HPV vaccination. The influence of culture on preferences for information sources, such as specific providers and provider gender, needs to be addressed. Programs designed to decrease barriers and improve HPV vaccination among Chinese students should also focus on acculturation status.

Vascular Endothelial Growth Factor C (VEGF-C) Sensitizes Lymphatic Endothelial Cells to Oxidative-Stress-Induced Apoptosis through DNA Damage and Mitochondrial Dysfunction: Implications for Lymphedema.

Secondary lymphedema is caused by damage to the lymphatic system from surgery, cancer treatment, infection, trauma, or obesity. This damage induces stresses such as oxidative stress and hypoxia in lymphatic tissue, impairing the lymphatic system. In response to damage, vascular endothelial growth factor C (VEGF-C) levels increase to induce lymphangiogenesis. Unfortunately, VEGF-C often fails to repair the lymphatic damage in lymphedema. The underlying mechanism contributing to lymphedema is not well understood. In this study, we found that surgery-induced tail lymphedema in a mouse model increased oxidative damage and cell death over 16 days. This corresponded with increased VEGF-C levels in mouse tail lymphedema tissue associated with macrophage infiltration. Similarly, in the plasma of patients with secondary lymphedema, we found a positive correlation between VEGF-C levels and redox imbalance. To determine the effect of oxidative stress in the presence or absence of VEGF-C, we found that hydrogen peroxide (H2O2) induced cell death in human dermal lymphatic endothelial cells (HDLECs), which was potentiated by VEGF-C. The cell death induced by VEGF-C and H2O2 in HDLECs was accompanied by increased reactive oxygen species (ROS) levels and a loss of mitochondrial membrane potential. Antioxidant pre-treatment rescued HDLECs from VEGF-C-induced cell death and decreased ROS under oxidative stress. As expected, VEGF-C increased the number of viable and proliferating HDLECs. However, upon H2O2 treatment, VEGF-C failed to increase either viable or proliferating cells. Since oxidative stress leads to DNA damage, we also determined whether VEGF-C treatment induces DNA damage in HDLECs undergoing oxidative stress. Indeed, DNA damage, detected in the form of gamma H2AX (γH2AX), was increased by VEGF-C under oxidative stress. The potentiation of oxidative stress damage induced by VEFG-C in HDLECs was associated with p53 activation. Finally, the inhibition of vascular endothelial growth factor receptor-3 (VEGFR-3) activation blocked VEGF-C-induced cell death following H2O2 treatment. These results indicate that VEGF-C further sensitizes lymphatic endothelial cells to oxidative stress by increasing ROS and DNA damage, potentially compromising lymphangiogenesis.

Enantioselective Multifunctionalization with Rh Carbynoids.

Multifunctionalization from the interception of active intermediates is an attractive synthetic strategy for the efficient construction of complex molecular scaffolds in an atom and step economic fashion. However, the design of reactions involving metal carbynoids that exhibit carbene/carbocation behavior is currently limited, and developing catalyst-controlled highly enantioselective versions poses significant challenges. In this study, we present the first asymmetric trifunctionalization reactions with rhodium carbynoids. This reaction unveils the distinctive reactivity of the carbynoid precursor, enabling it to react with simultaneously two nucleophiles and one electrophile. This process involves the formation of two distinct carbene ylides with the alcohol/carbamate and the trapping of one ylide with the imine, resulting in the formation of three new bonds. Furthermore, this strategy allows for the divergent synthesis of a wide array of ß-amino esters in high yields and exceptional enantioselectivity.