Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 737
Filter
1.
Histol Histopathol ; : 18765, 2024 May 20.
Article in English | MEDLINE | ID: mdl-38841987

ABSTRACT

BACKGROUND: This study was designed to explore whether hsa_circ_0070440 was dysregulated in prostate cancer (PCa), and assess the effects of hsa_circ_0070440 alteration on PCa prognosis and cell function. METHODS: The expression levels of hsa_circ_0070440 were assessed in PCa tissues and cell lines. After the classification of patients with PCa based on mean hsa_circ_0070440 level in 138 cases, Chi-square test and survival analyses (Kaplan-Meier method and multivariable Cox proportional hazards analysis) were performed to assess the predictive value of hsa_circ_0070440 in treatment failure (TTF), time to PSA progression (TTPP) and overall survival time. To examine the function of hsa_circ_0070440 in PCa cells, 22Rv1 and C4-2B cells were used for CCK-8 proliferation and Transwell migration assays. Hsa_circ_0070440- and TXNDC5-specific bindings with miR-382/383-5p were validated by bioinformatic analysis and luciferase gene reporter assay. RESULTS: An increased expression of hsa_circ_0070440 was found in PCA tissues and cell lines, associated with clinical T stage (p=0.021) and lymph node metastasis. Hsa_circ_0070440 predicted poor overall survival, TTPP, and TTF, acting as independent prognostic factors for overall survival, TTPP, and TTF in patients with PCa. Knockdown of hsa_circ_0070440 inhibited cell proliferation and migration in vitro. Furthermore, hsa_circ_0070440 could sponge miR-382/383-5p. TXNDC5 was a common target gene for miR-382/383-5p in PCa cells. CONCLUSION: This study demonstrated that hsa_circ_0070440 can predict the prognosis of PCa patients. Hsa_circ_0070440 can facilitate the proliferation and migration of PCa cells, possibly by sponging miR-382/383-5p.

2.
Adv Biol (Weinh) ; : e2400120, 2024 Jun 12.
Article in English | MEDLINE | ID: mdl-38864263

ABSTRACT

Triptolide (TP), an active component isolated from the traditional Chinese herb Tripterygium wilfordii Hook F (TWHF), shows great promise for treating inflammation-related diseases. However, its potential nephrotoxic effects remain concerning. The mechanism underlying TP-induced nephrotoxicity is inadequately elucidated, particularly at single-cell resolution. Hence, single-cell RNA sequencing (scRNA-seq) of kidney tissues from control and TP-treated mice is performed to generate a thorough description of the renal cell atlas upon TP treatment. Heterogeneous responses of nephron epithelial cells are observed after TP exposure, attributing differential susceptibility of cell subtypes to excessive reactive oxygen species and increased inflammatory responses. Moreover, TP disrupts vascular function by activating endothelial cell immunity and damaging fibroblasts. Severe immune cell damage and the activation of pro-inflammatory Macro_C1 cells are also observed with TP treatment. Additionally, ligand-receptor crosstalk analysis reveals that the SPP1 (osteopontin) signaling pathway targeting Macro_C1 cells is triggered by TP treatment, which may promote the infiltration of Macro_C1 cells to exacerbate renal toxicity. Overall, this study provides comprehensive information on the transcriptomic profiles and cellular composition of TP-associated nephrotoxicity at single-cell resolution, which can strengthen the understanding of the pathogenesis of TP-induced nephrotoxicity and provide valuable clues for the discovery of new therapeutic targets to ameliorate TP-associated nephrotoxicity.

3.
J Environ Sci (China) ; 145: 164-179, 2024 Nov.
Article in English | MEDLINE | ID: mdl-38844317

ABSTRACT

The occurrence of poisoning incidents caused by cyanobacterial blooms has aroused wide public concern. Microcystin-leucine arginine (MC-LR) is a well-established toxin produced by cyanobacterial blooms, which is widely distributed in eutrophic waters. MC-LR is not only hazardous to the water environment but also exerts multiple toxic effects including liver toxicity in both humans and animals. However, the underlying mechanisms of MC-LR-induced liver toxicity are unclear. Herein, we used advanced single-cell RNA sequencing technology to characterize MC-LR-induced liver injury in mice. We established the first single-cell atlas of mouse livers in response to MC-LR. Our results showed that the differentially expressed genes and pathways in diverse cell types of liver tissues of mice treated with MC-LR are highly heterogeneous. Deep analysis showed that MC-LR induced an increase in a subpopulation of hepatocytes that highly express Gstm3, which potentially contributed to hepatocyte apoptosis in response to MC-LR. Moreover, MC-LR increased the proportion and multiple subtypes of Kupffer cells with M1 phenotypes and highly expressed proinflammatory genes. Furthermore, the MC-LR increased several subtypes of CD8+ T cells with highly expressed multiple cytokines and chemokines. Overall, apart from directly inducing hepatocytes apoptosis, MC-LR activated proinflammatory Kupffer cell and CD8+ T cells, and their interaction may constitute a hostile microenvironment that contributes to liver injury. Our findings not only present novel insight into underlying molecular mechanisms but also provide a valuable resource and foundation for additional discovery of MC-LR-induced liver toxicity.


Subject(s)
Microcystins , Sequence Analysis, RNA , Microcystins/toxicity , Animals , Mice , Liver/drug effects , Marine Toxins/toxicity , Leucine , Hepatocytes/drug effects , Chemical and Drug Induced Liver Injury
4.
PLoS One ; 19(6): e0304689, 2024.
Article in English | MEDLINE | ID: mdl-38875285

ABSTRACT

To explore cost-effective and efficient phytoremediation strategies, this study investigated the distinct roles of earthworm activity and mucus in enhancing Cd phytoextraction from soils contaminated by Festuca arundinacea, focusing on the comparative advantages of selective leaf harvesting versus traditional whole-plant harvesting methods. Our study employed a horticultural trial to explore how earthworm activity and mucus affect Festuca arundinacea' s Cd phytoremediation in soils using control, earthworm, and mucus treatments to examine their respective effects on plant growth and Cd distribution. Earthworm activity increased the dry weight of leaves by 13.5% and significantly increased the dry weights of declining and senescent leaves, surpassing that of the control by more than 40%. Earthworm mucus had a similar, albeit less pronounced, effect on plant growth than earthworm activity. This study not only validated the significant role of earthworm activity in enhancing Cd phytoextraction by Festuca arundinacea, with earthworm activity leading to over 85% of Cd being allocated to senescent tissues that comprise only approximately 20% of the plant biomass, but also highlighted a sustainable and cost-effective approach to phytoremediation by emphasizing selective leaf harvesting supported by earthworm activity. By demonstrating that earthworm mucus alone can redistribute Cd with less efficiency compared to live earthworms, our findings offer practical insights into optimizing phytoremediation strategies and underscore the need for further research into the synergistic effects of biological agents in soil remediation processes.


Subject(s)
Biodegradation, Environmental , Cadmium , Festuca , Mucus , Oligochaeta , Plant Leaves , Soil Pollutants , Animals , Oligochaeta/metabolism , Oligochaeta/physiology , Cadmium/metabolism , Plant Leaves/metabolism , Festuca/metabolism , Soil Pollutants/metabolism , Mucus/metabolism , Biomass , Soil/chemistry
5.
Small Methods ; : e2400358, 2024 Jun 16.
Article in English | MEDLINE | ID: mdl-38880776

ABSTRACT

Assessing programmed death ligand-1 (PD-L1) expression in non-small cell lung cancer (NSCLC), particularly in metastatic cases, remains challenging. In this study, surface plasmon resonance (SPR) analysis and [68Ga]Ga-DOTA-WL12 micro-PET/CT imaging are performed. [68Ga]Ga-DOTA-WL12 PET/CT and [18F]FDG PET/CT are performed on a cohort of 20 patients with NSCLC. Semi-quantitative assessments include SUVmax, metabolic tumor volume (MTV), total lesion glycolysis (TLG), and target-to-background ratio (TBR). DOTA-WL12 exhibits robust PD-L1 binding with a KD value of 0.2 nM. Subsequent human studies reveal significant correlations between PD-L1 expression and the [68Ga]Ga-DOTA-WL12 SUVmax in primary and metastatic lesions, surpassing the [18F]FDG results (r = 0.8889, p <0.0001 vs r = 0.0469, p = 0.8127). Notably, [68Ga]Ga-DOTA-WL12 imaging discerned SUVmax and TBR differences between PD-L1 TPS ≤1% and PD-L1 TPS > 1% groups (p all <0.001). In an NSCLC patient with brain metastases, [68Ga]Ga-DOTA-WL12 shows a SUVmean of 0.04 in the brain background, with TBR values of 17 and 23, underscoring its potential for detecting brain metastases. The study provides initial evidence for the clinical utility of [68Ga]Ga-DOTA-WL12 PET/CT for lesion detection, immunotherapy selection, and therapeutic efficacy evaluation in PD-L1-expressing NSCLC, demonstrating its potential as a valuable tool in NSCLC research and management.

6.
JACS Au ; 4(5): 1935-1940, 2024 May 27.
Article in English | MEDLINE | ID: mdl-38818075

ABSTRACT

Chiral N-alkoxy amines are increasingly vital substrates in bioscience. However, asymmetric synthetic strategies for these compounds remain scarce. Catalytic kinetic resolution represents an attractive approach to prepare structurally diverse enantiopure N-alkoxy amines, which has remained elusive due to the notably reduced nucleophilicity of the nitrogen atom together with the low bond dissociation energies of labile NO-C and N-O bonds. We here report a general kinetic resolution of N-alkoxy amines through chemo- and enantioselective oxygenation. The mild and green titanium-catalyzed approach features broad substrate scope (55 examples), noteworthy functional group compatibility, high catalyst turnover number (up to 5200), excellent selectivity factor (s > 150), and scalability.

8.
Int J Biol Macromol ; 271(Pt 2): 132442, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38761903

ABSTRACT

During the pathogenesis of rheumatoid arthritis, inflammatory cells usually infiltrate synovial tissues, notably, M1-type macrophages, whose redox imbalance leads to the degradation of joint structures and deterioration of function. Natural active products play a vital role in immune modulation and antioxidants. In this study, we constructed a ROS-responsive nanoparticle called FTL@SIN, which consists of fucoidan (Fuc) and luteolin (Lut) connected by a ROS-responsive bond, Thioketal (TK), and encapsulated with an anti-rheumatic drug, Sinomenine (SIN), for synergistic anti-inflammatory effects. The FTL@SIN is then dispersed in high molecular weight Fuc-fabricated dissolvable microneedles (FTL@SIN MNs) for local administration. Therapy of FTL@SIN MNs afforded a significant decrease in macrophage inflammation while decreasing key pro-inflammatory cytokines and repolarizing M1 type to M2 type, thereby ameliorating synovial inflammation, and promoting cartilage repair. Additionally, our investigations have revealed that Fucoidan (Fuc) demonstrates synergistic effects, exhibiting superior mechanical strength and enhanced physical stability when compared to microneedles formulated solely with hyaluronic acid. This study combines nanomedicine with traditional Chinese medicine, a novel drug delivery strategy that presents a promising avenue for therapeutic intervention in rheumatoid arthritis.


Subject(s)
Arthritis, Rheumatoid , Macrophages , Needles , Polysaccharides , Reactive Oxygen Species , Polysaccharides/pharmacology , Polysaccharides/chemistry , Polysaccharides/administration & dosage , Animals , Arthritis, Rheumatoid/drug therapy , Arthritis, Rheumatoid/metabolism , Mice , Reactive Oxygen Species/metabolism , Macrophages/metabolism , Macrophages/drug effects , Polymers/chemistry , RAW 264.7 Cells , Inflammation/drug therapy , Humans , Nanoparticles/chemistry , Drug Delivery Systems , Cytokines/metabolism , Morphinans
10.
Fish Shellfish Immunol ; 149: 109604, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38710343

ABSTRACT

MicroRNAs (miRNAs) are a crucial type of non-coding RNAs involved in post-transcriptional regulation. The playing essential regulatory roles in the NF-κB signaling pathway and modulate the host immune response to diverse pathogens by targeting IκBα. However, the regulatory mechanism of miRNAs in relation with IκBα in Sebastes schlegelii remains unclear. In our study, we identified two copies of IkBα gene in black rockfish (Sebastes schlegelii), namely IkBα1 and IkBα2. Moreover, we have discovered that miRNA-530 can activate the NF-κB signaling pathway by inhibiting the expression of IκBα, thereby inducing the inflammatory response. This project comprehensively investigated the interactive regulatory roles of miRNA-530 in the NF-κB signaling pathway at both cellular and in vivo levels, while also elucidating the regulatory relationships between miRNA-530 and IκBα. In conclusion, our research confirmed that miRNA-530 can target the 3'UTR region of IκBα, resulting in a decrease in the expression of IκBα at the post-transcriptional level and inhibiting its translation. The findings contribute to the understanding of the regulatory network of non-coding RNA in teleosts and its subsequent regulation of the NF-κB signaling pathway by miRNAs.


Subject(s)
Gene Expression Regulation , MicroRNAs , NF-KappaB Inhibitor alpha , NF-kappa B , Signal Transduction , MicroRNAs/genetics , MicroRNAs/metabolism , Animals , NF-kappa B/genetics , NF-kappa B/metabolism , NF-KappaB Inhibitor alpha/genetics , NF-KappaB Inhibitor alpha/metabolism , Gene Expression Regulation/immunology , Fish Proteins/genetics , Fish Proteins/immunology , Immunity, Innate/genetics , Fishes/genetics , Fishes/immunology , Perciformes/genetics , Perciformes/immunology
11.
Int J Gen Med ; 17: 1909-1921, 2024.
Article in English | MEDLINE | ID: mdl-38736671

ABSTRACT

Background: Dilated cardiomyopathy (DCM) is a severe heterogeneous cardiomyopathy characterized by cardiac enlargement and declining heart function, often leading to refractory heart failure and life-threatening outcomes, particularly prevalent in China. The challenge lies in the scarcity of targeted therapies with substantial efficacy for DCM. Additionally, traditional anti-heart failure drugs are constrained due to hypotension propensity or limited symptom improvement. Kuoxin Formula (KXF), internally endorsed at Longhua Hospital, demonstrates clear biological evidence for enhancing cardiac function and myocardial remodeling. Previous clinical studies suggest its potential to enhance patients' quality of life. This trial aims to further evaluate KXF's safety and efficacy in managing DCM-related heart failure. Methods: This prospective, randomized, double-blind, placebo-controlled, multicenter trial aims to recruit 230 DCM patients from five centers. Participants will be randomly assigned to either KXF or placebo for 12 weeks, with careful monitoring of key indicators and adverse events. The primary outcome measures the proportion of patients with NT-proBNP reduction exceeding 30%. Secondary outcomes include New York Heart Association functional classification, Traditional Chinese Medicine syndrome scores, 6-minute walk test, Lee's heart failure score, and Minnesota Heart Failure Quality of Life Scale score. Ventricular remodeling will be assessed using cardiac ultrasound and ELISA. Safety metrics and adverse events will be meticulously recorded. Discussion: This study will be the first multicentered research conducted in China that utilizes a randomized, double-blind, placebo-controlled design to investigate the use of TCM in the treatment of DCM. It seeks to develop new theoretical frameworks and provide solid clinical data to support the integration of TCM and modern medicine in treating heart failure in DCM patients. Trial Registration: China Clinical Trial Registry, ChiCTR2300068937. Registered on March 1, 2023. https://www.chictr.org.cn/bin/project/edit?pid=190926.

12.
Sensors (Basel) ; 24(9)2024 Apr 30.
Article in English | MEDLINE | ID: mdl-38732977

ABSTRACT

Label-free measurement and analysis of single bacterial cells are essential for food safety monitoring and microbial disease diagnosis. We report a microwave flow cytometric sensor with a microstrip sensing device with reduced channel height for bacterial cell measurement. Escherichia coli B and Escherichia coli K-12 were measured with the sensor at frequencies between 500 MHz and 8 GHz. The results show microwave properties of E. coli cells are frequency-dependent. A LightGBM model was developed to classify cell types at a high accuracy of 0.96 at 1 GHz. Thus, the sensor provides a promising label-free method to rapidly detect and differentiate bacterial cells. Nevertheless, the method needs to be further developed by comprehensively measuring different types of cells and demonstrating accurate cell classification with improved machine-learning techniques.


Subject(s)
Escherichia coli , Flow Cytometry , Microwaves , Flow Cytometry/methods , Escherichia coli/isolation & purification , Biosensing Techniques/methods , Biosensing Techniques/instrumentation
13.
J Chromatogr A ; 1725: 464962, 2024 Jun 21.
Article in English | MEDLINE | ID: mdl-38704923

ABSTRACT

Because of the "enterohepatic circulation" of bile acid, liver damage can be reflected by monitoring the content of bile acid in the serum of the organism. To monitor the concentration of 15 bile acids in plasma samples, a new technique of PRiME (process, ruggedness, improvement, matrix effect, ease of use) pass-through cleanup procedure combined with high performance liquid chromatography-tandem quadrupole mass spectrometry (HPLC-MS/MS) was developed. The sorbent used in the PRiME pass-through cleanup procedure is a new type of magnetic organic resin composite nano-material modified by C18 (C18-PS-DVB-GMA-Fe3O4), which has high cleanup efficiency of plasma samples. It also shows good performance in the separation and analysis of 15 kinds of bile acids. Under the optimal conditions, the results show higher cleanup efficiency of C18-PS-DVB-GMA-Fe3O4 with recoveries in the range of 82.1-115 %. The limit of quantitative (LOQs) of 15 bile acids were in the range of 0.033 µg/L-0.19 µg/L, and the RSD values of 15 bile acids were in the range of 3.00-11.9 %. Validation results on linearity, specificity, accuracy and precision, as well as on the application to analysis of 15 bile acids in 100 human plasma samples demonstrate the applicability to clinical studies.


Subject(s)
Bile Acids and Salts , Limit of Detection , Nanocomposites , Tandem Mass Spectrometry , Humans , Bile Acids and Salts/blood , Bile Acids and Salts/chemistry , Tandem Mass Spectrometry/methods , Nanocomposites/chemistry , Chromatography, High Pressure Liquid/methods , Reproducibility of Results , Polymers/chemistry , Magnetite Nanoparticles/chemistry
14.
Biotechnol Lett ; 2024 May 11.
Article in English | MEDLINE | ID: mdl-38733437

ABSTRACT

Chiral epichlorohydrin (ECH) is an attractive intermediate for chiral pharmaceuticals and chemicals preparation. The asymmetric synthesis of chiral ECH using 1,3-dicholoro-2-propanol (1,3-DCP) catalyzed by a haloalcohol dehalogenase (HHDH) was considered as a feasible approach. However, the reverse ring opening reaction caused low optical purity of chiral ECH, thus severely restricts the industrial application of HHDHs. In the present study, a novel selective conformation adjustment strategy was developed with an engineered HheCPS to regulate the kinetic parameters of the forward and reverse reactions, based on site saturation mutation and molecular simulation analysis. The HheCPS mutant E85P was constructed with a markable change in the conformation of (S)-ECH in the substrate pocket and a slight impact on the interaction between 1,3-DCP and the enzyme, which resulted in the kinetic deceleration of the reverse reactions. Compared with HheCPS, the catalytic efficiency (kcat(S)-ECH/Km(S)-ECH) of the reversed reaction dropped to 0.23-fold (from 0.13 to 0.03 mM-1 s-1), while the catalytic efficiency (kcat(1,3-DCP)/Km(1,3-DCP)) of the forward reaction only reduced from 0.83 to 0.71 mM-1 s-1. With 40 mM 1,3-DCP as substrate, HheCPS E85P catalyzed the synthesis of (S)-ECH with the yield up to 55.35% and the e.e. increased from 92.54 to >99%. Our work provided an effective approach for understanding the stereoselective catalytic mechanism as well as the green manufacturing of chiral epoxides.

15.
Cancer Imaging ; 24(1): 58, 2024 May 07.
Article in English | MEDLINE | ID: mdl-38715096

ABSTRACT

BACKGROUND: In the present study, we investigated the value of 18F-fibroblast-activation protein inhibitor (FAPI) positron emission tomography/computed tomography (18F-FAPI-42 PET/CT) to preoperative evaluations of appendiceal neoplasms and management for patients. METHODS: This single-center retrospective clinical study, including 16 untreated and 6 treated patients, was performed from January 2022 to May 2023 at Southern Medical University Nanfang Hospital. Histopathologic examination and imaging follow-up served as the reference standard. 18F-FAPI-42 PET/CT was compared to 18F-fluorodeoxyglucose (18F-FDG) PET/CT and contrast-enhanced CT (CE-CT) in terms of maximal standardized uptake value (SUVmax), diagnostic efficacy and impact on treatment decisions. RESULTS: The accurate detection of primary tumors and peritoneal metastases were improved from 28.6% (4/14) and 50% (8/16) for CE-CT, and 43.8% (7/16) and 85.0% (17/20) for 18F-FDG PET/CT, to 87.5% (14/16) and 100% (20/20) for 18F-FAPI-42 PET/CT. Compared to 18F-FDG PET/CT, 18F-FAPI-42 PET/CT detected more regions infiltrated by peritoneal metastases (108 vs. 43), thus produced a higher peritoneal cancer index (PCI) score (median PCI: 12 vs. 5, P < 0.01). 18F-FAPI-42 PET/CT changed the intended treatment plans in 35.7% (5/14) of patients compared to CE-CT and 25% (4/16) of patients compared to 18F-FDG PET/CT but did not improve the management of patients with recurrent tumors. CONCLUSIONS: The present study revealed that 18F-FAPI-42 PET/CT can supplement CE-CT and 18F-FDG PET/CT to provide a more accurate detection of appendiceal neoplasms and improved treatment decision making for patients.


Subject(s)
Appendiceal Neoplasms , Fluorodeoxyglucose F18 , Positron Emission Tomography Computed Tomography , Radiopharmaceuticals , Humans , Positron Emission Tomography Computed Tomography/methods , Female , Male , Retrospective Studies , Middle Aged , Appendiceal Neoplasms/diagnostic imaging , Appendiceal Neoplasms/pathology , Appendiceal Neoplasms/therapy , Aged , Adult , Peritoneal Neoplasms/diagnostic imaging , Peritoneal Neoplasms/therapy , Peritoneal Neoplasms/secondary , Tomography, X-Ray Computed/methods
16.
EMBO Mol Med ; 16(5): 1143-1161, 2024 May.
Article in English | MEDLINE | ID: mdl-38565806

ABSTRACT

Accurately predicting and selecting patients who can benefit from targeted or immunotherapy is crucial for precision therapy. Trophoblast cell surface antigen 2 (Trop2) has been extensively investigated as a pan-cancer biomarker expressed in various tumours and plays a crucial role in tumorigenesis through multiple signalling pathways. Our laboratory successfully developed two 68Ga-labelled nanobody tracers that can rapidly and specifically target Trop2. Of the two tracers, [68Ga]Ga-NOTA-T4, demonstrated excellent pharmacokinetics in preclinical mouse models and a beagle dog. Moreover, [68Ga]Ga-NOTA-T4 immuno-positron emission tomography (immunoPET) allowed noninvasive visualisation of Trop2 heterogeneous and differential expression in preclinical solid tumour models and ten patients with solid tumours. [68Ga]Ga-NOTA-T4 immunoPET could facilitate clinical decision-making through patient stratification and response monitoring during Trop2-targeted therapies.


Subject(s)
Antigens, Neoplasm , Cell Adhesion Molecules , Neoplasms , Positron-Emission Tomography , Antigens, Neoplasm/metabolism , Antigens, Neoplasm/immunology , Humans , Animals , Cell Adhesion Molecules/metabolism , Neoplasms/diagnostic imaging , Neoplasms/immunology , Mice , Dogs , Positron-Emission Tomography/methods , Female , Single-Domain Antibodies/immunology
17.
Oecologia ; 205(1): 39-48, 2024 May.
Article in English | MEDLINE | ID: mdl-38652293

ABSTRACT

Ecologists have historically sought to identify the mechanisms underlying the maintenance of local species diversity. High-dimensional trait-based relationships, such as alternative phenotypes, have been hypothesized as important for maintaining species diversity such that phenotypically dissimilar individuals compete less for resources but have similar performance in a given environment. The presence of alternative phenotypes has primarily been investigated at the community level, despite the importance of intraspecific variation to diversity maintenance. The aims of this research are to (1) determine the presence or absence of intraspecific alternative phenotypes in three species of tropical tree seedlings, (2) investigate if these different species use the same alternative phenotypes for growth success, and (3) evaluate how findings align with species co-occurrence patterns. We model species-specific relative growth rate with individual-level measurements of leaf mass per area (LMA) and root mass fraction (RMF), environmental data, and their interactions. We find that two of the three species have intraspecific alternative phenotypes, with individuals within species having different functional forms leading to similar growth. Interestingly, individuals within these species use the same trait combinations, high LMA × low RMF and low LMA × high RMF, in high soil nutrient environments to acquire resources for higher growth. This similarity among species in intraspecific alternative phenotypes and variables that contribute most to growth may lead to their negative spatial co-occurrence. Overall, we find that multiple traits or interactions between traits and the environment drive species-specific strategies for growth, but that individuals within species leverage this multi-dimensionality in different ways for growth success.


Subject(s)
Phenotype , Trees/growth & development , Plant Leaves/growth & development , Seedlings/growth & development , Species Specificity
18.
Sci Adv ; 10(17): eadm7737, 2024 Apr 26.
Article in English | MEDLINE | ID: mdl-38669331

ABSTRACT

Flat membranes ubiquitously transform into mysterious complex shapes in nature and artificial worlds. Behind the complexity, clear determinative deformation modes have been continuously found to serve as basic application rules but remain unfulfilled. Here, we decipher two elemental deformation modes of thin membranes, spontaneous scrolling and folding as passing through shrinking channels. We validate that these two modes rule the deformation of membranes of a wide thickness range from micrometer to atomic scale. Their occurrence and the determinative fold number quantitatively correlate with the Föppl-von Kármán number and shrinkage ratio. The unveiled determinative deformation modes can guide fabricating foldable designer microrobots and delicate structures of two-dimensional sheets and provide another mechanical principle beyond genetic determinism in biological morphogens.

19.
Cardiovasc Diabetol ; 23(1): 126, 2024 Apr 13.
Article in English | MEDLINE | ID: mdl-38614964

ABSTRACT

BACKGROUND: The accumulation of visceral and ectopic fat comprise a major cause of cardiometabolic diseases. However, novel drug targets for reducing unnecessary visceral and ectopic fat are still limited. Our study aims to provide a comprehensive investigation of the causal effects of the plasma proteome on visceral and ectopic fat using Mendelian randomization (MR) approach. METHODS: We performed two-sample MR analyses based on five large genome-wide association study (GWAS) summary statistics of 2656 plasma proteins, to screen for causal associations of these proteins with traits of visceral and ectopic fat in over 30,000 participants of European ancestry, as well as to assess mediation effects by risk factors of outcomes. The colocalization analysis was conducted to examine whether the identified proteins and outcomes shared casual variants. RESULTS: Genetically predicted levels of 14 circulating proteins were associated with visceral and ectopic fat (P < 4.99 × 10- 5, at a Bonferroni-corrected threshold). Colocalization analysis prioritized ten protein targets that showed effect on outcomes, including FST, SIRT2, DNAJB9, IL6R, CTSA, RGMB, PNLIPRP1, FLT4, PPY and IL6ST. MR analyses revealed seven risk factors for visceral and ectopic fat (P < 0.0024). Furthermore, the associations of CTSA, DNAJB9 and IGFBP1 with primary outcomes were mediated by HDL-C and SHBG. Sensitivity analyses showed little evidence of pleiotropy. CONCLUSIONS: Our study identified candidate proteins showing putative causal effects as potential therapeutic targets for visceral and ectopic fat accumulation and outlined causal pathways for further prevention of downstream cardiometabolic diseases.


Subject(s)
Adiposity , Cardiovascular Diseases , Humans , Adiposity/genetics , Proteome , Genome-Wide Association Study , Mendelian Randomization Analysis , Obesity , Membrane Proteins , Molecular Chaperones , HSP40 Heat-Shock Proteins
20.
J Immunother Cancer ; 12(4)2024 Apr 05.
Article in English | MEDLINE | ID: mdl-38580333

ABSTRACT

BACKGROUND: The programmed cell death protein-1 (PD-1)/programmed death receptor ligand 1 (PD-L1) axis critically facilitates cancer cells' immune evasion. Antibody therapeutics targeting the PD-1/PD-L1 axis have shown remarkable efficacy in various tumors. Immuno-positron emission tomography (ImmunoPET) imaging of PD-L1 expression may help reshape solid tumors' immunotherapy landscape. METHODS: By immunizing an alpaca with recombinant human PD-L1, three clones of the variable domain of the heavy chain of heavy-chain only antibody (VHH) were screened, and RW102 with high binding affinity was selected for further studies. ABDRW102, a VHH derivative, was further engineered by fusing RW102 with the albumin binder ABD035. Based on the two targeting vectors, four PD-L1-specific tracers ([68Ga]Ga-NOTA-RW102, [68Ga]Ga-NOTA-ABDRW102, [64Cu]Cu-NOTA-ABDRW102, and [89Zr]Zr-DFO-ABDRW102) with different circulation times were developed. The diagnostic efficacies were thoroughly evaluated in preclinical solid tumor models, followed by a first-in-human translational investigation of [68Ga]Ga-NOTA-RW102 in patients with non-small cell lung cancer (NSCLC). RESULTS: While RW102 has a high binding affinity to PD-L1 with an excellent KD value of 15.29 pM, ABDRW102 simultaneously binds to human PD-L1 and human serum albumin with an excellent KD value of 3.71 pM and 3.38 pM, respectively. Radiotracers derived from RW102 and ABDRW102 have different in vivo circulation times. In preclinical studies, [68Ga]Ga-NOTA-RW102 immunoPET imaging allowed same-day annotation of differential PD-L1 expression with specificity, while [64Cu]Cu-NOTA-ABDRW102 and [89Zr]Zr-DFO-ABDRW102 enabled longitudinal visualization of PD-L1. More importantly, a pilot clinical trial shows the safety and diagnostic value of [68Ga]Ga-NOTA-RW102 immunoPET imaging in patients with NSCLCs and its potential to predict immune-related adverse effects following PD-L1-targeted immunotherapies. CONCLUSIONS: We developed and validated a series of PD-L1-targeted tracers. Initial preclinical and clinical evidence indicates that immunoPET imaging with [68Ga]Ga-NOTA-RW102 holds promise in visualizing differential PD-L1 expression, selecting patients for PD-L1-targeted immunotherapies, and monitoring immune-related adverse effects in patients receiving PD-L1-targeted treatments. TRIAL REGISTRATION NUMBER: NCT06165874.


Subject(s)
B7-H1 Antigen , Carcinoma, Non-Small-Cell Lung , Heterocyclic Compounds, 1-Ring , Lung Neoplasms , Single-Domain Antibodies , Humans , B7-H1 Antigen/drug effects , B7-H1 Antigen/metabolism , Carcinoma, Non-Small-Cell Lung/diagnostic imaging , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/pathology , Cell Line, Tumor , Gallium Radioisotopes , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Programmed Cell Death 1 Receptor , Single-Domain Antibodies/pharmacology , Single-Domain Antibodies/therapeutic use
SELECTION OF CITATIONS
SEARCH DETAIL
...