ABSTRACT
The prevalence of severe mental disorders has been rising annually. Electroconvulsive therapy (ECT) is considered a valuable treatment option in psychiatry for conditions such as schizophrenia and medication-resistant depression, especially when other treatments have proven insufficient. ECT rapidly improves patients' mood, alleviates symptoms, and demonstrates significant therapeutic effects. Currently, the form of ECT used in clinical practice is modified electroconvulsive therapy (mECT), which is administered under general anesthesia. Accumulative evidence has confirmed that different anesthetic drugs, anesthetic-ECT time interval, anesthetic depth, and airway management can impact the outcomes of ECT. Therefore, this review aims to summarize the current impact of anesthesia factors on ECT, providing reference for clinical anesthesia during ECT procedures.
ABSTRACT
Peptidyl arginine deiminase 4 (PAD4) plays a critical role in many autoimmune diseases including rheumatoid arthritis. Herein, a trypsin assisted highly immunoassay method was established to determine PAD4 activity and screen potent inhibitors from herbal plants extracts and purified natural products. The method was applied to determine endogenous PAD4 activity in both cell and tissue lysates, as well as the inhibitory effects of 20 herbal plants and 50 purified natural products. The Cinnamomi ramulus extract showed strongest inhibitory potency with IC50 value lower than 5 µg/mL. Meanwhile, pyrroloquinoline quinone (PQQ), widely used as a dietary supplement, was discovered as a promising PAD4 inhibitor with an IC50 value lower than 4 µM. The inhibition kinetic analysis, drug affinity response target stability (DARTS) and molecular docking were performed to confirm the interaction between PQQ and PAD4. This method has great potential for researchers to monitor activities and discover potential inhibitors of PAD4.
ABSTRACT
Among various factors related to the forest carbon pool, the tree stand age, which interacts with soil organic matter, decomposition rates, and microbial activity, is essential and cannot be disregarded. However, knowledge about how tree phases influence soil carbon sinks is not adequate. This study sampled Larix kaempferi (Japanese larch) plantations with different tree stand ages to investigate the temporal dynamics of soil carbon sink in the forest. Physiochemical analyses and high-throughput sequencing results further revealed the interactions of tree stands and their related rhizosphere microbiome. It was found that microbial composition and metabolic activity were significantly affected by different tree ages, whose structures gradually diversified and became more stable from young to mature forests. Many keystone taxa from the phyla Chloroflexi, Proteobacteria, Acidobacteriota, and Nitrospirota were found to be associated with carbon transformation processes. Interestingly, the carbon resource utilization strategies of microbial groups related to tree ages also differed, with near-mature forest soils showing better labile carbon degradation capacity, and mature forests possessing higher degradation potential of recalcitrant carbon. Age-altered tree growth and physiology were found to interact with its rhizosphere microbiome, which is the driving factor in the formation and stability of forest soil carbon. This study highlighted that the tree age-associated soil microbiomes, which provided insights into their effects on soil carbon transformation, were significant in enhancing the knowledge of carbon sequestration in L. kaempferi plantations.
ABSTRACT
Dysregulation of peptidyl arginine deiminase 4 (PAD4) is involved in a variety of diseases including rheumatoid arthritis (RA) and Alzheimer's disease (AD), and it has emerged as potential and promising therapeutic target. However, no PAD4 inhibitor is ready for clinical use. Immobilized enzyme screening technology has gained increasing attention due to its low cost, reusability, easy separation from the reaction mixture, and resistance to changes in environmental conditions. In this study, PAD4 was immobilized on the magnetic nanoparticles (MNP) to prolong its activity stability, and a simple and rapid screening strategy of traditional Chinese medicine inhibitors based on immobilized PAD4 was established. The PAD4 enzyme was immobilized on magnetic nanoparticles (MNP) via Schiff base reaction using glutaraldehyde (GA) as crosslinking agent. Compared with free PAD4, the resulting MNP@GA@PAD4 exhibited an enhanced tolerance to temperature and storage stability, and its reusability was greatly improved with 66 % of initial enzyme activity after being recycled 10 times. The inhibitory activity of the immobilized PAD4 was assessed using two known PAD4 inhibitors GSK484 and BB-Cl-amidine. The semi-maximum inhibitory concentrations (IC50) of GSK484 and BB-Cl-amidine for MNP@GA@PAD4 were 1.00 and 0.97 µM, respectively, for free PAD4 were 0.64 and 0.85 µM, respectively. Finally, the MNP@GA@PAD4 was employed to rapid screen of natural PAD4 inhibitors from forty traditional Chinese medicines (TCMs). Under the same conditions, the controlled experiment was conducted with free PAD4. The screening results of TCMs inhibitors on MNP@GA@PAD4 and free PAD4 were similar, the alcohol extracts of Cinnamomi Cortex and Caryophylli Flos had significant inhibitory effects on PAD4 enzyme activity. The IC50 values of Cinnamomi Cortex extract for MNP@GA@PAD4 and free PAD4 were determined as 27 and 48 µg/mL, respectively. The IC50 values of Caryophylli Flos extracts for MNP@GA@PAD4 and free PAD4 were determined as 48 and 32 µg/mL, respectively. For the first time, this study proposed a method to immobilize PAD4 on magnetic materials, and developed a rapid, reusable and feasible strategy to screening natural PAD4 inhibitors from TCMs.
Subject(s)
Enzyme Inhibitors , Enzymes, Immobilized , Magnetite Nanoparticles , Protein-Arginine Deiminase Type 4 , Enzymes, Immobilized/chemistry , Enzymes, Immobilized/metabolism , Enzymes, Immobilized/antagonists & inhibitors , Magnetite Nanoparticles/chemistry , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Protein-Arginine Deiminase Type 4/antagonists & inhibitors , Protein-Arginine Deiminase Type 4/metabolism , Protein-Arginine Deiminase Type 4/chemistry , Humans , Medicine, Chinese Traditional , Drugs, Chinese Herbal/chemistry , Drugs, Chinese Herbal/pharmacology , Drug Evaluation, PreclinicalABSTRACT
Protein citrullination is an irreversible post-translational modification process regulated by peptidylarginine deiminases (PADs) in the presence of Ca2+. This process is closely related to the occurrence and development of autoimmune diseases, cancers, neurological disorders, cardiovascular and cerebrovascular diseases, and other major diseases. The analysis of protein citrullination by biomass spectrometry confronts great challenges owing to its low abundance, lack of affinity tags, small mass-to-charge ratio change, and susceptibility to isotopic and deamidation interferences. The methods commonly used to study the protein citrullination mainly involve the chemical derivatization of the urea group of the guanine side chain of the peptide to increase the mass-to-charge ratio difference of the citrullinated peptide. Affinity-enriched labels are then introduced to effectively improve the sensitivity and accuracy of protein citrullination by mass spectrometry. 2,3-Butanedione or phenylglyoxal compounds are often used as derivatization reagents to increase the mass-to-charge ratio difference of the citrullinated peptide, and the resulting derivatives have been observed to contain α-dicarbonyl structures. To date, however, no relevant studies on the reactivity of dicarbonyl compounds with citrullinated peptides have been reported. In this study, we determined whether six α-dicarbonyl and two ß-dicarbonyl compounds undergo derivatization reactions with standard citrullinated peptides using matrix-assisted laser desorption ionization-time-of-flight mass spectrometry (MALDI-TOF MS). Among the α-dicarbonyl compounds, 2,3-butanedione and glyoxal reacted efficiently with several standard citrullinated peptides, but yielded a series of by-products. Phenylglyoxal, methylglyoxal, 1,2-cyclohexanedione, and 1,10-phenanthroline-5,6-dione also derivated efficiently with standard citrullinated peptides, generating a single derivative. Thus, a new derivatization method that could yield a single derivative was identified. Among the ß-dicarbonyl compounds, 1,3-cyclohexanedione and 2,4-pentanedione successfully reacted with the standard citrullinated peptides, and generated a single derivative. However, their reaction efficiency was very low, indicating that the ß-dicarbonyl compounds are unsuitable for the chemical derivatization of citrullinated peptides. The above results indicate that the α-dicarbonyl structure is necessary for realizing the efficient and specific chemical derivatization of citrullinated peptides. Moreover, the side chains of the α-dicarbonyl structure determine the structure of the derivatives, derivatization efficiency, and generation (or otherwise) of by-products. Therefore, the specific enrichment and precise identification of citrullinated peptides can be achieved by synthesizing α-dicarbonyl structured compounds containing affinity tags. The proposed method enables the identification of citrullinated proteins and their modified sites by MS, thereby providing a better understanding of the distribution of citrullinated proteins in different tissues. The findings will be beneficial for studies on the mechanism of action of citrullinated proteins in a variety of diseases.
Subject(s)
Citrullination , Peptides , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization/methods , Peptides/chemistryABSTRACT
Background: Microsatellite instability (MSI) secondary to mismatch repair (MMR) deficiency is characterized by insertions and deletions (indels) in short DNA sequences across the genome. These indels can generate neoantigens, which are ideal targets for precision immune interception. However, current neoantigen databases lack information on neoantigens arising from coding microsatellites. To address this gap, we introduce The MicrOsatellite Neoantigen Discovery Tool (MONET). Method: MONET identifies potential mutated tumor-specific neoantigens (neoAgs) by predicting frameshift mutations in coding microsatellite sequences of the human genome. Then MONET annotates these neoAgs with key features such as binding affinity, stability, expression, frequency, and potential pathogenicity using established algorithms, tools, and public databases. A user-friendly web interface (https://monet.mdanderson.org/) facilitates access to these predictions. Results: MONET predicts over 4 million and 15 million Class I and Class II potential frameshift neoAgs, respectively. Compared to existing databases, MONET demonstrates superior coverage (>85% vs. <25%) using a set of experimentally validated neoAgs. Conclusion: MONET is a freely available, user-friendly web tool that leverages publicly available resources to identify neoAgs derived from microsatellite loci. This systems biology approach empowers researchers in the field of precision immune interception.
Subject(s)
Antigens, Neoplasm , Databases, Genetic , Microsatellite Repeats , Humans , Microsatellite Repeats/genetics , Antigens, Neoplasm/genetics , Antigens, Neoplasm/immunology , Microsatellite Instability , Frameshift Mutation , Software , Computational Biology/methods , Neoplasms/genetics , Neoplasms/immunologyABSTRACT
PURPOSE: To retrospectively evaluate the tislelizumab-based chemoimmunotherapy combined with gemcitabine/cisplatin for bladder-sparing in patients with muscle-invasive bladder cancer (MIBC). METHODS: Forty-five patients who received bladder-sparing treatment or radical cystectomy (RC) for MIBC (cT2-T4a, NxM0) were retrospectively enrolled. All patients received maximal transurethral resection of bladder tumor (mTURBT), followed by four cycles of chemo-immunotherapy with tislelizumab (PD-L1 inhibitor), gemcitabine, and cisplatin. Clinical efficacy was evaluated to compare the benefit of bladder-sparing treatment on clinical CR (cCR) and RC for non-cCR patients. The primary outcomes were bladder intact disease-free survival (BIDFS) and overall survival (OS), and the secondary outcomes were adverse effects. The PD-L1 status and molecular subtypes of tumors were analyzed. RESULTS: The overall survival rate was 88.8% (95%CI: 79.6%, 98.0%) at 12 months, 85.7% (95%CI: 74.9%, 96.5%) at 18 months, and 66.6% (95%CI: 45.2%, 88.0%) at 24 months. Twenty-nine patients (64.4%) achieved cCR and their OS rate was 96.6% (95%CI: 89.9%, 100%). Sixteen patients were in the non-cCR group, and their OS rate was 75.0% (95%CI: 53.8%, 96.2%) at 12 months, 65.6% (95%CI: 40.3%, 90.9%) at 18 months, and 52.5% (95%CI: 21.9%, 83.1%) at 24 months. The BIDFS rate for patients who received bladder-sparing treatment was 96.0% (95%CI: 88.4%, 100%) from 12 to 24 months. Four patients (8.8%) were PD-L1 positive and 41 patients (91.2%) were PD-L1 negative. CONCLUSIONS: Our retrospective study of patients with MIBC suggests that tislelizumab-based neoadjuvant therapy was a safe and effective bladder-sparing treatment.
Subject(s)
Antibodies, Monoclonal, Humanized , Antineoplastic Combined Chemotherapy Protocols , Cisplatin , Cystectomy , Deoxycytidine , Gemcitabine , Neoplasm Invasiveness , Urinary Bladder Neoplasms , Humans , Urinary Bladder Neoplasms/drug therapy , Urinary Bladder Neoplasms/pathology , Urinary Bladder Neoplasms/mortality , Male , Female , Retrospective Studies , Aged , Cisplatin/administration & dosage , Cisplatin/therapeutic use , Deoxycytidine/analogs & derivatives , Deoxycytidine/administration & dosage , Deoxycytidine/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Middle Aged , Antibodies, Monoclonal, Humanized/therapeutic use , Antibodies, Monoclonal, Humanized/administration & dosage , Organ Sparing Treatments/methods , Survival Rate , Adult , Aged, 80 and overABSTRACT
The accumulation of unfolded or misfolded proteins within the endoplasmic reticulum (ER), due to genetic determinants and extrinsic environmental factors, leads to endoplasmic reticulum stress (ER stress). As ER stress ensues, the unfolded protein response (UPR), comprising three signaling pathways-inositol-requiring enzyme 1, protein kinase R-like endoplasmic reticulum kinase, and activating transcription factor 6 promptly activates to enhance the ER's protein-folding capacity and restore ER homeostasis. However, prolonged ER stress levels propels the UPR towards cellular demise and the subsequent inflammatory cascade, contributing to the development of human diseases, including cancer, neurodegenerative disorders, and diabetes. Notably, increased expression of all three UPR signaling pathways has been observed in these pathologies, and reduction in signaling molecule expression correlates with decreased proliferation of disease-associated target cells. Consequently, therapeutic strategies targeting ER stress-related interventions have attracted significant research interest. In this review, we elucidate the critical role of ER stress in cancer, metabolic, and neurodegenerative diseases, offering novel therapeutic approaches for these conditions.
Subject(s)
Neoplasms , Neurodegenerative Diseases , Humans , Neurodegenerative Diseases/therapy , Endoplasmic Reticulum Stress/genetics , Unfolded Protein Response , Signal Transduction , Neoplasms/therapyABSTRACT
Constructed wetlands are an efficient and cost-effective method of restoring degraded wetlands, in which the microorganisms present make a significant contribution to the ecosystem. In this study, we comprehensively investigated the patterns of diversity and assembly processes of 7 types of constructed wetlands at the rhizosphere and phyllosphere levels. The results showed that the rhizosphere communities of the constructed wetlands exhibited a more balanced structure than that of paddy fields, and 5 types of constructed wetland demonstrated higher potential diversity than that of paddy fields. However, the opposite trend was observed for the phyllosphere communities. Analysis of mean nearest taxon difference indicated that both deterministic and stochastic processes affected the establishment of the rhizosphere and phyllosphere communities, and stochastic processes may have had a larger effect. An iCAMP model showed that dispersal limitation was the most important factor (67% relative contribution) in the rhizosphere community, while drift was the most important (47% relative contribution) in the phyllosphere community. Mantel tests suggested that sucrase, average height, top height, total biomass, belowground biomass, maximum water-holding capacity, and capillary porosity were significantly correlated with processes in the rhizosphere community, whereas factors such as the deterministic process, average height, top height, and SOC were significantly correlated with deterministic processes in the phyllosphere community. Our results can assist in the evaluation of artificial restorations, and can provide understanding of the ecological processes of microbial communities, as well as new insights into the manipulation of microorganisms in polluted wetland ecosystems.
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Cortex-like cytoskeleton, a thin layer of cross-linked cytoplasmic proteins underlying the cell membrane, plays an essential role in modulating membrane behavior and cell surface properties. However, bottom-up construction of functional cortex-like cytoskeleton in artificial cells remains a challenge. Here, we present metal-phenolic networks as artificial cortical cytoskeletons in liposome-based artificial cells. The metal-phenolic cytoskeleton-reinforced artificial cells exhibit long-term stability, enhanced resistance to a variety of harsh environments, tunable permeability, and well-controlled morphologies. We anticipate that our stable artificial cell models will stride forward to practical applications of liposome-based microsystem.
Subject(s)
Artificial Cells , Liposomes/metabolism , Cytoskeleton/metabolism , Microtubules , Cell Membrane/metabolism , Metals/metabolismABSTRACT
To elucidate the role of nitric oxide synthase (NOS), which produces the free radical nitric oxide (NO), and nicotinamide adenine dinucleotide phosphate oxidase (NOX), which produces the superoxide anion (O2-), in the innate immunity of Eriocheir sinensis, the full lengths of the NOS and NOX genes were cloned via rapid amplification of the cDNA ends and then expressed in the prokaryotic form to obtain the recombinant proteins, NOS-HIS and NOX-HIS. Through bacterial binding and stimulation experiments, the molecular mechanisms of NOS and NOX in the innate immunity of E. sinensis were explored. Based on the results, NOS and NOX were 5900 bp and 4504 bp long, respectively, and were evolutionarily conserved. Quantitative real-time PCR revealed that NOS and NOX were expressed in all studied tissues, and both were expressed in the highest amounts in hemocytes. NOS-HIS and NOX-HIS could bind to bacteria with different binding powers; their binding ability to gram-positive bacteria was higher than that of binding to gram-negative bacteria. After stimulation with Aeromonas hydrophila, NOS expression was significantly up-regulated at 3, 6, and 48 h, and NOX expression was significantly down-regulated at 3, 12, 24, and 48 h. After bacterial stimulation, the NOS enzyme activity in the serum of E. sinensis was also significantly up-regulated at 6 and 48 h, and the NOX enzyme activity was significantly down-regulated at 12 and 48 h, aligning with the gene expression trend. Moreover, the related free radical molecules, NO, O2-, and H2O2, tended to decrease after bacterial stimulation. Overall, the gene expression and enzyme activity of NOS and NOX had been changed respectively, and the contents of a series of free radical molecules (NO, O2- and H2O2) were induced in E. sinensis after bacterial stimulation, which then exert antibacterial immunity.
Subject(s)
Brachyura , Hydrogen Peroxide , Animals , Hydrogen Peroxide/pharmacology , Nitric Oxide Synthase/genetics , Nitric Oxide Synthase/metabolism , Anti-Bacterial Agents/pharmacology , Recombinant Proteins/genetics , Bacteria/metabolism , Brachyura/genetics , Immunity, Innate , Phylogeny , Arthropod Proteins/genetics , Hemocytes/metabolismABSTRACT
BACKGROUND & AIMS: Lynch syndrome (LS) carriers develop mismatch repair-deficient neoplasia with high neoantigen (neoAg) rates. No detailed information on targetable neoAgs from LS precancers exists, which is crucial for vaccine development and immune-interception strategies. We report a focused somatic mutation and frameshift-neoAg landscape of microsatellite loci from colorectal polyps without malignant potential (PWOMP), precancers, and early-stage cancers in LS carriers. METHODS: We generated paired whole-exome and transcriptomic sequencing data from 8 colorectal PWOMP, 41 precancers, 8 advanced precancers, and 12 early-stage cancers of 43 LS carriers. A computational pipeline was developed to predict, rank, and prioritize the top 100 detected mutated neoAgs that were validated in vitro using ELISpot and tetramer assays. RESULTS: Mutation calling revealed >10 mut/Mb in 83% of cancers, 63% of advanced precancers, and 20% of precancers. Cancers displayed an average of 616 MHC-I neoAgs/sample, 294 in advanced precancers, and 107 in precancers. No neoAgs were detected in PWOMP. A total of 65% of our top 100 predicted neoAgs were immunogenic in vitro, and were present in 92% of cancers, 50% of advanced precancers, and 29% of precancers. We observed increased levels of naïve CD8+ and memory CD4+ T cells in mismatch repair-deficient cancers and precancers via transcriptomics analysis. CONCLUSIONS: Shared frameshift-neoAgs are generated within unstable microsatellite loci at initial stages of LS carcinogenesis and can induce T-cell responses, generating opportunities for vaccine development, targeting LS precancers and early-stage cancers.
Subject(s)
Antigens, Neoplasm , Colorectal Neoplasms, Hereditary Nonpolyposis , Exome Sequencing , Frameshift Mutation , Humans , Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , Colorectal Neoplasms, Hereditary Nonpolyposis/immunology , Antigens, Neoplasm/immunology , Antigens, Neoplasm/genetics , Female , Mutation , Male , Middle Aged , DNA Mismatch Repair/genetics , Microsatellite Repeats , Microsatellite Instability , Colorectal Neoplasms/genetics , Colorectal Neoplasms/immunology , Colorectal Neoplasms/prevention & control , Adult , Cancer Vaccines/immunology , Cancer Vaccines/therapeutic useABSTRACT
Thrombophlebitis is the inflammatory condition characterized by obstruction of one or more vessels, commonly in the legs, due to the formation of blood clots. It has been reported that traditional Chinese medicine, including Mailuoning injection, is advantageous for treating inflammatory and blood disorders. This research assessed the therapeutic efficacy of Mailuoning injection in the treatment of thrombophlebitis in rodents, as well as investigated its impact on fibrinolysis, inflammation, and coagulation. An experimental setup for thrombophlebitis was established in rodents via modified ligation technique. Five groups comprised the animals: sham operation group, model group, and three Mailuoning treatment groups (low, medium, and high dosages). The pain response, edema, coagulation parameters (PT, APTT, TT, FIB), serum inflammatory markers (IL-6, TNF-α, CRP), and expression levels of endothelial markers (ICAM-1, VCAM-1, NF-κB) were evaluated. Blood flow and vascular function were further assessed by measuring hemorheological parameters and the concentrations of TXB2, ET, and 6-k-PGF1α. In contrast to the sham group, model group demonstrated statistically significant increases in endothelial expression levels, coagulation latencies, and inflammatory markers (p < 0.05). The administration of mailing, specifically at high and medium dosages, resulted in a substantial reduction in inflammatory markers, enhancement of coagulation parameters, suppression of ICAM-1 and VCAM-1 expression, and restoration of hemorheological measurements to baseline (p < 0.05). Significantly higher concentrations of 6-k-PGF1α and lower levels of TXB2 and ET were observed in high-dose group, suggesting that pro- and anti-thrombotic factors were restored to equilibrium. Utilization of Mailuoning injection in rat model of thrombophlebitis exhibited significant therapeutic impact. This effect was manifested through pain alleviation, diminished inflammation, enhanced blood viscosity and facilitation of fibrinolysis. The study indicated that Mailuoning injection may serve as a viable therapeutic option for thrombophlebitis, potentially aiding in the improvement of wound healing by virtue of its anti-inflammatory and blood flow-enhancing characteristics.
Subject(s)
Drugs, Chinese Herbal , Intercellular Adhesion Molecule-1 , Thrombophlebitis , Rats , Animals , Intercellular Adhesion Molecule-1/metabolism , Vascular Cell Adhesion Molecule-1/metabolism , Wound Healing , Inflammation/drug therapy , Thrombophlebitis/drug therapy , PainSubject(s)
Vena Cava Filters , Venous Thrombosis , Humans , Extremities , Vena Cava, Inferior , Venous Thrombosis/surgeryABSTRACT
Apoptosis Inhibitor 5 (API5) is a widely concerned nuclear protein with diverse functions in organisms, so far, study of API5 is still quite limited in lower animals, and its role in viral immune response has not been addressed. Here, we explored the function of API5 in mud crab (Scylla paramamosain) during White Spot Syndrome Virus (WSSV) infection. The interacting protein Hsp20 of API5 was screened by pull-down assay, and API5 and hsp20 were knocked down by RNAi interference. The results showed that API5 was upregulated along with virus infection, silencing of API5 led to increased WSSV copy numbers and apoptotic rate of hemocytes, highlighting its significance in the immune response. Moreover, we discovered a novel interaction between API5 and Heat Shock Protein 20 (Hsp20), and then revealed that Hsp20 could promote cell apoptosis of hemocytes and reduce viral copy numbers by suppressing API5. The current study therefore improves the knowledge of API5-Hsp20 axis and provides novel insights into intricate mechanisms governing the antiviral response in marine crustaceans.
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As a vital component of arbor forests, understory vegetation serves as an essential buffer zone for storing carbon due to its strong capacity for community regeneration. This study aimed to identify the diversity pattern and construction mechanism of Platycladus orientalis and Pinus elliottii understory vegetation based on large-scale sample surveys. The Bayesian Information Criterion value of species abundance distribution (SAD) indicated that the Zipf and Zipf-Mandelbrot models were the best-fitting models. The SAD and gambin fitting results suggested that the Pi. elliottii community had a more balanced structure, with most species being relatively abundant. The multiple regression tree model detected four and six indicator species in P. orientalis and Pi. elliottii communities, respectively. The α-diversity index increased with a rise in altitude and showed a wavy curve with latitude. Linear regression between the ß diversity and environmental and geographic distance indicated that the P. orientalis and Pi. elliottii understory communities tended to be dominated by different ecological processes. The partition of ß diversity indicated that both communities were dominated by turnover processes, which were caused by environmental classification or spatial constraints. This study helped to understand the diversity maintenance in the P. orientalis and Pi. elliottii understory vegetation communities, and will benefit for diversity restoration and conservation of pure conifer forests.
ABSTRACT
Cronkhite-Canada Syndrome (CCS) is a rare, noninherited polyposis syndrome affecting 1 in every million individuals. Despite over 50 years of CCS cases, the etiopathogenesis and optimal treatment for CCS remains unknown due to the rarity of the disease and lack of model systems. To better understand the etiology of CCS, we generated human intestinal organoids (HIOs) from intestinal stem cells isolated from 2 patients. We discovered that CCS HIOs are highly proliferative and have increased numbers of enteroendocrine cells producing serotonin (also known as 5-hydroxytryptamine or 5HT). These features were also confirmed in patient tissue biopsies. Recombinant 5HT increased proliferation of non-CCS donor HIOs and inhibition of 5HT production in the CCS HIOs resulted in decreased proliferation, suggesting a link between local epithelial 5HT production and control of epithelial stem cell proliferation. This link was confirmed in genetically engineered HIOs with an increased number of enteroendocrine cells. This work provides a new mechanism to explain the pathogenesis of CCS and illustrates the important contribution of HIO cultures to understanding disease etiology and in the identification of novel therapies. Our work demonstrates the principle of using organoids for personalized medicine and sheds light on how intestinal hormones can play a role in intestinal epithelial proliferation.
Subject(s)
Colorectal Neoplasms , Intestinal Polyposis , Humans , Serotonin , Intestines , Organoids/pathology , Colorectal Neoplasms/pathology , Intestinal Polyposis/genetics , Intestinal Polyposis/pathologyABSTRACT
Solid-state electrolytes (SSEs) based on metal organic framework (MOF) and polymer mixed matrix membranes (MMMs) have shown great promotions in both lithium-ion conduction and interfacial resistance in lithium metal batteries (LMBs). However, the unwanted structural evolution and the and the obscure electrochemical reaction mechanism among two phases limit their further optimization and commercial application. Herein, fluorine-modified zirconium MOF with diverse F-quantities is synthesized, denoted as Zr-BDC-Fx (x = 0, 2, 4), to assemble high performance quais-solid-state electrolytes (QSSEs) with PVDF-HFP. The chemical complexation of F-sites in Zr-BDC-F4 stabilized PVDF-HFP chains in ß-phase and disordered oscillation with enhanced charge transfer and Li transmit property. Besides, the porous confinement and electronegativity of F-groups enhanced the capture and dissociation of TFSI- anions and the homogeneous deposition of LiF solid electrolyte interphase (SEI), promoting the high-efficient transport of Li+ ions and inhibiting the growth of Li dendrites. The superb specific capacities in high-loaded Li.
ABSTRACT
PURPOSE: Lynch syndrome (LS) is a hereditary condition with a high lifetime risk of colorectal and endometrial cancers. Exercise is a non-pharmacologic intervention to reduce cancer risk, though its impact on patients with LS has not been prospectively studied. Here, we evaluated the impact of a 12-month aerobic exercise cycling intervention in the biology of the immune system in LS carriers. PATIENTS AND METHODS: To address this, we enrolled 21 patients with LS onto a non-randomized, sequential intervention assignation, clinical trial to assess the effect of a 12-month exercise program that included cycling classes 3 times weekly for 45 minutes versus usual care with a one-time exercise counseling session as control. We analyzed the effects of exercise on cardiorespiratory fitness, circulating, and colorectal-tissue biomarkers using metabolomics, gene expression by bulk mRNA sequencing, and spatial transcriptomics by NanoString GeoMx. RESULTS: We observed a significant increase in oxygen consumption (VO2peak) as a primary outcome of the exercise and a decrease in inflammatory markers (prostaglandin E) in colon and blood as the secondary outcomes in the exercise versus usual care group. Gene expression profiling and spatial transcriptomics on available colon biopsies revealed an increase in the colonic mucosa levels of natural killer and CD8+ T cells in the exercise group that were further confirmed by IHC studies. CONCLUSIONS: Together these data have important implications for cancer interception in LS, and document for the first-time biological effects of exercise in the immune system of a target organ in patients at-risk for cancer.
Subject(s)
Colorectal Neoplasms, Hereditary Nonpolyposis , Endometrial Neoplasms , Female , Humans , Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , Colorectal Neoplasms, Hereditary Nonpolyposis/therapy , Exercise , Endometrial Neoplasms/genetics , Gene Expression Profiling , Intestinal Mucosa/pathologyABSTRACT
Structural colors show diverse advantages such as fade resistance, eco-friendliness, iridescence, and high saturation in comparison with chemical pigments. In this paper, we show tunable structural coloration in colorless water-in-oil-in-water double emulsion droplets via total internal reflection and interference at the microscale concave interfaces. Through experimental work and simulations, we demonstrate that the shell thickness and the eccentricity of the core-shell structures are key to the successful formation of iridescent structural colors. Only eccentric thin-shell water-in-oil-in-water droplets show structural colors. Importantly, structural colors based on water-oil interfaces are readily responsive to a variety of environmental stimuli, such as osmotic pressure, temperature, magnetic fields, and light composition. This work highlights an alternative structural coloration that expands the applications of droplet-based structural colors to aqueous systems.