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1.
Cancer ; 130(S8): 1415-1423, 2024 Apr 15.
Article in English | MEDLINE | ID: mdl-38079306

ABSTRACT

BACKGROUND: Immune-checkpoint blockade (ICB) therapy shows promise for treating aggressive triple-negative breast cancer (TNBC). However, only some patients benefit from ICB, revealing an urgent need for identifying novel strategies for sensitizing patients to ICB. Previously, the authors demonstrated that type-I protein arginine methyltransferases (PRMTs) regulated antiviral innate-immune responses in TNBC by altering RNA splicing. This study aimed to explore the effects of targeting type-I PRMTs on the tumor microenvironment (TME) and the efficacy of ICB therapy against TNBC. METHODS: Single-cell transcriptomic analysis was performed to investigate the effects of type-I PRMT inhibition on the TME, especially T-cell subsets. Single-cell T-cell receptor sequencing was performed to analyze the diversity and dynamics of the T-cell repertoire. A syngeneic murine model of TNBC was used to evaluate the therapeutic efficacy and immune memory effect of combining a type-I PRMT inhibitor (MS023) with an anti-programmed cell death protein 1 (PD-1) antibody. RESULTS: Type-I PRMT inhibition combined with anti-PD-1 therapy reduced tumor growth. Mechanistically, type-I PRMT inhibition reshaped the TME. Increased CD8 T-cell infiltration was verified using flow cytometry. Increased clonotypes and clonal diversity were also observed after MS023 treatment, which contributed to immune memory following combination treatment. CONCLUSIONS: Targeting type-I PRMT can potentially improve immunotherapeutic efficacies in patients with TNBC. By enhancing the tumor immunogenicity and promoting a more favorable immune microenvironment, this combined approach may enable more patients with TNBC to benefit from immunotherapies.


Subject(s)
Triple Negative Breast Neoplasms , Humans , Animals , Mice , Triple Negative Breast Neoplasms/drug therapy , Triple Negative Breast Neoplasms/genetics , Programmed Cell Death 1 Receptor , Protein-Arginine N-Methyltransferases/genetics , Immunotherapy , Cell Death , Tumor Microenvironment
2.
Clin Endocrinol (Oxf) ; 100(3): 294-303, 2024 03.
Article in English | MEDLINE | ID: mdl-38214116

ABSTRACT

This study aimed to evaluate whether there is a causal relationship between autoimmune thyroid disorders (AITDs) and telomere length (TL) in the European population and whether there is reverse causality. In this study, Mendelian randomization (MR) and colocalization analysis were conducted to assess the potential causal relationship between AITDs and TL using summary statistics from large-scale genome-wide association studies, followed by analysis of the relationship between TL and thyroid stimulating hormone and free thyroxine (FT4) to help interpret the findings. The inverse variance weighted (IVW) method was used to estimate the causal estimates. The weighted median, MR-Egger and leave-one-out methods were used as sensitivity analyses. The IVW method results showed a significant causal relationship between autoimmune hyperthyroidism and TL (ß = -1.93 × 10-2 ; p = 4.54 × 10-5 ). There was no causal relationship between autoimmune hypothyroidism and TL (ß = -3.99 × 10-3 ; p = 0.324). The results of the reverse MR analysis showed that genetically TL had a significant causal relationship on autoimmune hyperthyroidism (IVW: odds ratio (OR) = 0.49; p = 2.83 × 10-4 ) and autoimmune hypothyroidism (IVW: OR = 0.86; p = 7.46 × 10-3 ). Both horizontal pleiotropy and heterogeneity tests indicated the validity of our bidirectional MR study. Finally, colocalization analysis suggested that there were shared causal variants between autoimmune hyperthyroidism and TL, further highlighting the robustness of the results. In conclusion, autoimmune hyperthyroidism may accelerate telomere attrition, and telomere attrition is a causal factor for AITDs.


Subject(s)
Graves Disease , Hashimoto Disease , Hypothyroidism , Thyroiditis, Autoimmune , Humans , Genome-Wide Association Study , Mendelian Randomization Analysis , Telomere/genetics , Hypothyroidism/genetics
3.
Theor Appl Genet ; 137(2): 39, 2024 Jan 31.
Article in English | MEDLINE | ID: mdl-38294546

ABSTRACT

KEY MESSAGE: Two major genetic loci, qTN5.1 and qAB9.1, were identified and finely mapped to the 255 Kb region with one potential candidate gene for tiller number and the 521 Kb region with eight candidate genes for axillary branch number, respectively. Vegetative branching including tillering and axillary branching are vital traits affecting both the plant architecture and the biomass in cereal crops. However, the mechanism underlying the formation of vegetative branching in foxtail millet is largely unknown. Here, a foxtail millet cultivar and its bushy wild relative Setaria viridis accession were used to construct segregating populations to identify candidate genes regulating tiller number and axillary branch number. Transcriptome analysis using vegetative branching bud samples of parental accessions was performed, and key differentially expressed genes and pathways regulating vegetative branching were pointed out. Bulk segregant analysis on their F2:3 segregating population was carried out, and a major QTL for tiller number (qTN5.1) and two major QTLs for axillary branch number (qAB2.1 and qAB9.1) were detected. Fine-mapping strategy was further performed on F2:4 segregate population, and Seita.5G356600 encoding ß-glucosidase 11 was identified as the promising candidate gene for qTN5.1, and eight genes, especially Seita.9G125300 and Seita.9G125400 annotated as B-S glucosidase 44, were finally identified as candidate genes for regulating axillary branching. Findings in this study will help to elucidate the genetic basis of the vegetative branching formation of foxtail millet and lay a foundation for breeding foxtail millet varieties with ideal vegetative branching numbers.


Subject(s)
Setaria Plant , Setaria Plant/genetics , Plant Breeding , Gene Expression Profiling , Transcriptome , Quantitative Trait Loci
4.
Biomed Chromatogr ; 38(2): e5782, 2024 Feb.
Article in English | MEDLINE | ID: mdl-38016814

ABSTRACT

Natural medicines play a crucial role in clinical drug applications, serving as a primary traditional Chinese medicine for the clinical treatment of liver fibrosis. Understanding the in vivo metabolic process of the Fuzheng Huayu (FZHY) formula is essential for delving into its material basis and mechanism. In recent years, there has been a growing body of research focused on the mechanisms and component analysis of FZHY. This study aimed to examine the pharmacokinetics of FZHY in healthy volunteers following oral administration. Blood samples were collected at designated time intervals after the oral intake of 9.6-g FZHY tablets. A UHPLC-Q/Exactive method was developed to assess the plasma concentrations of five components post-FZHY ingestion. The peak time for all components occurred within 10 min. The peak concentration (Cmax ) values for amygdalin, schisandrin, and schisandrin A ranged from 3.47 to 28.80 ng/mL, with corresponding AUC(0-t) values ranging from 10.63 to 103.20 ng h/mL. For schisandrin B and prunasin, Cmax values were in the range of 86.52 to 229.10 ng/mL, and their AUC(0-t) values ranged from 375.26 to 1875.54 ng h/mL, indicating significant exposure within the body. These findings demonstrate that the developed method enables rapid and accurate detection and quantification of the five components in FZHY, offering a valuable reference for its clinical study.


Subject(s)
Drugs, Chinese Herbal , Humans , Drugs, Chinese Herbal/pharmacokinetics , Liver Cirrhosis/drug therapy , Liver Cirrhosis/metabolism , Medicine, Chinese Traditional/methods , Administration, Oral , Tablets
5.
Molecules ; 29(5)2024 Feb 28.
Article in English | MEDLINE | ID: mdl-38474548

ABSTRACT

Transient receptor potential vanilloid 4 (TRPV4) is a widely expressed cation channel that plays an important role in many physiological and pathological processes. However, most TRPV4 drugs carry a risk of side effects. Moreover, existing screening methods are not suitable for the high-throughput screening (HTS) of drugs. In this study, a cell model and HTS method for targeting TRPV4 channel drugs were established based on a calcium-activated chloride channel protein 1 Anoctamin 1 (ANO1) and a double mutant (YFP-H148Q/I152L) of the yellow fluorescent protein (YFP). Patch-clamp experiments and fluorescence quenching kinetic experiments were used to verify that the model could sensitively detect changes in intracellular Ca2+ concentration. The functionality of the TRPV4 cell model was examined through temperature variations and different concentrations of TRPV4 modulators, and the performance of the model in HTS was also evaluated. The model was able to sensitively detect changes in the intracellular Ca2+ concentration and also excelled at screening TRPV4 drugs, and the model was more suitable for HTS. We successfully constructed a drug cell screening model targeting the TRPV4 channel, which provides a tool to study the pathophysiological functions of TRPV4 in vitro.


Subject(s)
High-Throughput Screening Assays , TRPV Cation Channels , TRPV Cation Channels/metabolism , Anoctamin-1 , Calcium/metabolism
6.
Biochem Biophys Res Commun ; 665: 55-63, 2023 07 12.
Article in English | MEDLINE | ID: mdl-37148745

ABSTRACT

Triple-negative breast cancer (TNBC) is a heterogeneous breast cancer subtype with poor prognoses and limited therapeutic options. The TATA-box binding protein associated factor 1 (TAF1) is an essential protein involved in the transcriptional regulation of cancer development and progress. However, the therapeutic potential and underlying mechanism of targeting TAF1 in TNBC remain unknown. Here, using chemical probe BAY-299, we identify that TAF1 inhibition leads to the induction of endogenous retrovirus (ERVs) expression and double-stranded RNA (dsRNA) formation, resulting in the activation of interferon responses and cell growth suppression in a subset of TNBC, resembling anti-viral mimicry effect. This correlation between TAF1 and interferon signature was validated in three independent breast cancer patient datasets. Furthermore, we observe heterogeneous responses to TAF1 inhibition across a set of TNBC cell lines. By integrating transcriptome and proteome data, we demonstrate that high levels of proliferating cell nuclear antigen (PCNA) protein serve as a predictive biomarker associated with suppressive tumor immune responses in various cancers, which may limit the efficiency of TAF1 inhibition.


Subject(s)
Triple Negative Breast Neoplasms , Humans , Cell Cycle , Cell Line, Tumor , Cell Proliferation , Interferons/pharmacology , Transcriptome , Triple Negative Breast Neoplasms/pathology
7.
BMC Endocr Disord ; 23(1): 1, 2023 Jan 03.
Article in English | MEDLINE | ID: mdl-36597121

ABSTRACT

BACKGROUND: Osteoporosis (OP) and diabetes mellitus (DM) are two major healthcare issues in the world. Numerous population based-studies have reported an increased prevalence of OP among individuals with DM, though, estimates vary significantly. PURPOSE: The objective of this study is to estimate the prevalence of OP in patients with DM. METHODS: To identify relevant literature, PubMed, Embase, Medline, CBM and Cochrane Library were searched for studies published from inception till July 2022, The search was conducted, and studies were included without countries and language restrictions. For full-text articles included in the study, the references were also independently searched. Random inverse variance-weighted models were used by Stata version 17.0 to estimate the prevalence of OP in patients with diabetes across studies. The heterogeneity was examined with I2 via the χ2 test on Cochrane's Q statistic. Subgroup analysis and meta-regression were used to explore potential sources of heterogeneity. Egger's test was used to assess publication bias. RESULTS: A high OP prevalence of 27.67% (95% confidence interval (CI) 21.37-33.98%) was found in a pooled analysis of 21 studies involving 11,603 T2DM patients. Methodological value of the included articles was high, with only three medium-quality studies and no low-quality studies. A significantly high heterogeneity (I2 = 98.5%) was observed. CONCLUSIONS: Worldwide, a high prevalence of OP was found in patients with T2DM. Therefore, strong measures to prevent and treat osteoporosis in diabetic patients are required. TRIAL REGISTRATION: This study has been registered on PROSPERO, number CRD42021286580 .


Subject(s)
Diabetes Mellitus, Type 2 , Osteoporosis , Humans , Prevalence , Osteoporosis/epidemiology , Osteoporosis/etiology , Research Design , Qualitative Research , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/epidemiology
8.
Article in English | MEDLINE | ID: mdl-38038762

ABSTRACT

Childhood maltreatment (CM) has been linked to social cognition deficits in major depressive disorder (MDD), but little is known about sex-specific effects. This study aimed to investigate the sex-specific associations of CM with social cognition in first-episode drug-naive patients with MDD. A total of 117 first-episode drug-naive patients with MDD and 134 healthy controls (HCs) were recruited and assessed for demographic and clinical characteristics. All participants completed the Childhood Trauma Questionnaire (CTQ), Toronto Alexithymia Scale (TAS-20), Interpersonal Reactivity Index-C (IRI), and Facial Emotion Recognition Test. Partial correlation analysis was used to explore the sex-specific association of CM with social cognition. Our findings revealed significant differences in the associations of CM with social cognition between males and females in MDD patients. In comparison to HCs, the associations of CM with social cognition displayed distinct and even contrasting sex-specific patterns in MDD patients. Specifically, male MDD patients exhibited unique imbalanced associations between emotional neglect and alexithymia, while both female and male MDD patients shared imbalanced associations of childhood abuse with empathy. These results emphasize the importance of considering the sex-specific associations of CM with social cognition in MDD and highlight the need for personalized interventions and treatments based on sex for MDD patients with a history of CM.

9.
J Nanobiotechnology ; 21(1): 221, 2023 Jul 12.
Article in English | MEDLINE | ID: mdl-37438800

ABSTRACT

Breast cancer bone metastasis has become a common cancer type that still lacks an effective treatment method. Although epigenetic drugs have demonstrated promise in cancer therapy, their nontargeted accumulation and drug resistance remain nonnegligible limiting factors. Herein, we first found that icaritin had a strong synergistic effect with an epigenetic drug (JQ1) in the suppression of breast cancer, which could help to relieve drug resistance to JQ1. To improve tumor-targeted efficacy, we developed a hypoxia-cleavable, RGD peptide-modified poly(D,L-lactide-co-glycolide) (PLGA) nanoparticle (termed ARNP) for the targeted delivery of JQ1 and icaritin. The decoration of long cleavable PEG chains can shield RGD peptides during blood circulation and reduce cellular uptake at nonspecific sites. ARNP actively targets breast cancer cells via an RGD-αvß3 integrin interaction after PEG chain cleavage by responding to hypoxic tumor microenvironment. In vitro and in vivo assays revealed that ARNP exhibited good biodistribution and effectively suppressed primary tumor and bone metastasis. Meanwhile, ARNP could alleviate bone erosion to a certain extent. Furthermore, ARNP significantly inhibited pulmonary metastasis secondary to bone metastasis. The present study suggests that ARNP has great promise in the treatment of breast cancer and bone metastasis due to its simple and practical potential.


Subject(s)
Bone Neoplasms , Nanomedicine , Humans , Pharmaceutical Preparations , Tissue Distribution , Bone Neoplasms/drug therapy , Epigenesis, Genetic , Tumor Microenvironment
10.
Sleep Breath ; 27(4): 1597-1610, 2023 08.
Article in English | MEDLINE | ID: mdl-36194363

ABSTRACT

In western medicine, obstructive sleep apnea hypopnea syndrome (OSAHS) is an increasingly serious public health hazard, which is exacerbated by the obesity epidemic and an aging population. Ancient medical literature of traditional Chinese medicine (TCM) also recorded OSAHS-like symptoms but described the disease from a completely distinct theoretical perspective. The earliest records of snoring in ancient China can be traced back 2500 years. In TCM, the pathogenesis of OSAHS can be attributed mainly to turbid phlegm and blood stasis. Various TCM prescriptions, herbal medicines, and external therapy have also been proposed for the prevention and therapy of OSAHS. Some of these strategies are still used in current clinical practice. This review highlights historical characterizations of OSAHS and the theory of TCM and also explores its therapy in TCM, which may shed light on future OSAHS research. This is the first systematic English review of the role of TCM in the treatment of OSAHS.


Subject(s)
Medicine, Chinese Traditional , Sleep Apnea, Obstructive , Humans , Aged , Polysomnography , Sleep Apnea, Obstructive/diagnosis , Sleep Apnea, Obstructive/epidemiology , Sleep Apnea, Obstructive/therapy , Syndrome , Respiratory Rate , Snoring/epidemiology , Snoring/therapy
11.
Proc Natl Acad Sci U S A ; 117(32): 19141-19150, 2020 08 11.
Article in English | MEDLINE | ID: mdl-32703811

ABSTRACT

Current strategies to direct therapy-loaded nanoparticles to the brain rely on functionalizing nanoparticles with ligands which bind target proteins associated with the blood-brain barrier (BBB). However, such strategies have significant brain-specificity limitations, as target proteins are not exclusively expressed at the brain microvasculature. Therefore, novel strategies which exploit alternative characteristics of the BBB are required to overcome nonspecific nanoparticle targeting to the periphery, thereby increasing drug efficacy and reducing detrimental peripheral side effects. Here, we present a simple, yet counterintuitive, brain-targeting strategy which exploits the higher impermeability of the BBB to selectively label the brain endothelium. This is achieved by harnessing the lower endocytic rate of brain endothelial cells (a key feature of the high BBB impermeability) to promote selective retention of free, unconjugated protein-binding ligands on the surface of brain endothelial cells compared to peripheral endothelial cells. Nanoparticles capable of efficiently binding to the displayed ligands (i.e., labeled endothelium) are consequently targeted specifically to the brain microvasculature with minimal "off-target" accumulation in peripheral organs. This approach therefore revolutionizes brain-targeting strategies by implementing a two-step targeting method which exploits the physiology of the BBB to generate the required brain specificity for nanoparticle delivery, paving the way to overcome targeting limitations and achieve clinical translation of neurological therapies. In addition, this work demonstrates that protein targets for brain delivery may be identified based not on differential tissue expression, but on differential endocytic rates between the brain and periphery.


Subject(s)
Blood-Brain Barrier/metabolism , Brain/metabolism , Drug Carriers/metabolism , Drug Delivery Systems/instrumentation , Endothelial Cells/metabolism , Nanoparticles/metabolism , Animals , Biological Transport , Brain/blood supply , Endothelium/metabolism , Humans , Rats , Rats, Sprague-Dawley
12.
Int J Mol Sci ; 24(14)2023 Jul 13.
Article in English | MEDLINE | ID: mdl-37511149

ABSTRACT

There have been outbreaks of SARS-CoV-2 around the world for over three years, and its variants continue to evolve. This has become a major global health threat. The main protease (Mpro, also called 3CLpro) plays a key role in viral replication and proliferation, making it an attractive drug target. Here, we have identified a novel potential inhibitor of Mpro, by applying the virtual screening of hundreds of nilotinib-structure-like compounds that we designed and synthesized. The screened compounds were assessed using SP docking, XP docking, MM-GBSA analysis, IFD docking, MD simulation, ADME/T prediction, and then an enzymatic assay in vitro. We finally identified the compound V291 as a potential SARS-CoV-2 Mpro inhibitor, with a high docking affinity and enzyme inhibitory activity. Moreover, the docking results indicate that His41 is a favorable amino acid for pi-pi interactions, while Glu166 can participate in salt-bridge formation with the protonated primary or secondary amines in the screened molecules. Thus, the compounds reported here are capable of engaging the key amino acids His41 and Glu166 in ligand-receptor interactions. A pharmacophore analysis further validates this assertion.


Subject(s)
COVID-19 , Humans , SARS-CoV-2 , Gene Library , Amines , Amino Acids , Molecular Docking Simulation , Protease Inhibitors/pharmacology , Molecular Dynamics Simulation
13.
Molecules ; 28(3)2023 Jan 29.
Article in English | MEDLINE | ID: mdl-36770956

ABSTRACT

Paeoniflorin is a glycoside compound found in Paeonia lactiflora Pall that is used in traditional herbal medicine and shows various protective effects on the cardio-cerebral vascular system. It has been reported that the pharmacological effects of paeoniflorin might be generated by its metabolites. However, the bioavailability of paeoniflorin by oral administration is low, which greatly limits its clinical application. In this paper, a paeoniflorin-converting enzyme gene (G6046, GenBank accession numbers: OP856858) from Cunninghamella blakesleeana (AS 3.970) was identified by comparative analysis between MS analysis and transcriptomics. The expression, purification, enzyme activity, and structure of the conversion products produced by this paeoniflorin-converting enzyme were studied. The optimal conditions for the enzymatic activity were found to be pH 9, 45 °C, resulting in a specific enzyme activity of 14.56 U/mg. The products were separated and purified by high-performance counter-current chromatography (HPCCC). Two main components were isolated and identified, 2-amino-2-p-hydroxymethyl-methyl alcohol-benzoate (tirs-benzoate) and 1-benzoyloxy-2,3-propanediol (1-benzoyloxypropane-2,3-diol), via UPLC-Q-TOF-MS and NMR. Additionally, paeoniflorin demonstrated the ability to metabolize into benzoic acid via G6046 enzyme, which might exert antidepressant effects through the blood-brain barrier into the brain.


Subject(s)
Cunninghamella , Paeonia , Glucosides/metabolism , Glycosides/metabolism , Cunninghamella/metabolism , Monoterpenes/chemistry , Benzoates/metabolism , Paeonia/chemistry
14.
Theor Appl Genet ; 135(10): 3661-3672, 2022 Oct.
Article in English | MEDLINE | ID: mdl-36085525

ABSTRACT

KEY MESSAGE: qSI07.1, a major QTL for seed index in cotton, was fine-mapped to a 17.45-kb region, and the candidate gene GhSI7 was verified in transgenic plants. Improving production to meet human needs is a vital objective in cotton breeding. The yield-related trait seed index is a complex quantitative trait, but few candidate genes for seed index have been characterized. Here, a major QTL for seed index qSI07.1 was fine-mapped to a 17.45-kb region by linkage analysis and substitutional mapping. Only GhSI7, encoding the transcriptional regulator STERILE APETALA, was contained in the candidate region. Association test and genetic analysis indicated that an 845-bp-deletion in its intron was responsible for the seed index variation. Origin analysis revealed that this variation was unique in Gossypium hirsutum and originated from race accessions. Overexpression of GhSI7 (haplotype 2) significantly increased the seed index and organ size in cotton plants. Our findings provided a diagnostic marker for breeding and selecting cotton varieties with high seed index, and laid a foundation for further studies to understand the molecular mechanism of cotton seed morphogenesis.


Subject(s)
Gossypium , Quantitative Trait Loci , Chromosome Mapping , Cotton Fiber , Gossypium/genetics , Humans , Phenotype , Plant Breeding , Plant Proteins , Seeds/genetics
15.
BMC Cardiovasc Disord ; 22(1): 58, 2022 02 17.
Article in English | MEDLINE | ID: mdl-35172721

ABSTRACT

BACKGROUND: The present study aimed to comprehensively investigate the occurrence and risk factors of adverse events (AEs) or adverse drug reactions (ADRs) (especially for thrombocytopenia and bleeding) in Chinese female patients receiving bivalirudin during percutaneous coronary intervention (PCI). METHODS: A total of 918 female patients from 27 Chinese medical centers took bivalirudin as anticoagulant for PCI were enrolled in this prospective, multi-center, intensive monitoring study. Safety data (AEs, ADRs, thrombocytopenia and bleeding) were collected from admission to 72 h post bivalirudin administration; then, patients were followed up at the 30th day with the safety data collected as well. RESULTS: One hundred and twenty (13.1%) patients occurred AEs, among which 7 (0.8%) cases experienced severe AEs, and 2 (0.2%) cases died. Besides, 40 (4.4%) patients occurred bivalirudin-related ADRs, in which 3 (0.3%) cases experienced severe ADRs, but 0 (0.0%) cases died. It was of note that 27 (2.9%) and 13 (1.4%) patients experienced thrombocytopenia and bleeding, respectively. Subsequent multivariate analyses observed that: clinical presentation of spontaneous coronary artery dissection (SCAD) (odds ratio (OR) = 3.191, P = 0.004), CRUSADE high risk (OR = 2.075, P = 0.031), multiple culprit vessel (OR = 2.328, P = 0.019) independently correlated with higher risk of bivalirudin-related ADRs; clinical presentation of SCAD (OR = 4.388, P = 0.002) and multiple culprit vessel (OR = 2.974, P = 0.010) independently linked with raised thrombocytopenia risk; history of diabetes mellitus (OR = 5.227, P = 0.007) and CRUSADE high risk (OR = 4.475, P = 0.016) were independent factor related to elevated bleeding risk. CONCLUSION: Bivalirudin is well tolerated with low ADRs, thrombocytopenia and bleeding incidences in Chinese female patients undergoing PCI.


Subject(s)
Antithrombins/therapeutic use , Coronary Artery Disease/therapy , Peptide Fragments/therapeutic use , Percutaneous Coronary Intervention , Aged , Antithrombins/adverse effects , China , Coronary Artery Disease/diagnosis , Coronary Artery Disease/epidemiology , Female , Hemorrhage/chemically induced , Hemorrhage/epidemiology , Hirudins/adverse effects , Humans , Incidence , Middle Aged , Peptide Fragments/adverse effects , Percutaneous Coronary Intervention/adverse effects , Prospective Studies , Recombinant Proteins/adverse effects , Recombinant Proteins/therapeutic use , Risk Assessment , Risk Factors , Sex Factors , Thrombocytopenia/chemically induced , Thrombocytopenia/epidemiology , Time Factors , Treatment Outcome
16.
J Phycol ; 58(5): 657-668, 2022 Oct.
Article in English | MEDLINE | ID: mdl-35757840

ABSTRACT

Macroalgae, particularly commercially grown seaweed, substantially contribute to CO2 removal and carbon storage. However, knowledge regarding the CO2 concentrating mechanism (CCM) of macroalgae is limited. Carbonic anhydrase (CA), a key component of the biophysical CCM, plays important roles in many physiological reactions in various organisms. Few characteristics of CA in Neopyropia yezoensis are known, particularly its intracellular location and responses to different concentrations of Ci. We identified, amplified, and characterized 11 putative genes encoding N. yezoensis CA. The predicted corresponding proteins clustered into three subfamilies: α-, ß-, and γ-type. The intracellular localization of seven CA isoforms-one in the chloroplasts, three in the cytoplasm, and three in the mitochondria-was elucidated with fusion proteins. Higher NyCA expression, particularly of certain chloroplastic, cytosolic, and mitochondrial CAs, is observed more often during the foliose stage, thus suggesting that CAs play important roles in development in N. yezoensis.


Subject(s)
Carbonic Anhydrases , Carbon/metabolism , Carbon Dioxide/metabolism , Carbonic Anhydrases/genetics , Carbonic Anhydrases/metabolism , Chloroplasts , Protein Isoforms/metabolism
17.
Molecules ; 27(9)2022 May 07.
Article in English | MEDLINE | ID: mdl-35566353

ABSTRACT

P2Y receptors are G-protein-coupled receptors (GPCRs) for extracellular nucleotides. The P2Y2 receptor subtype is expressed in a variety of cell types and plays an important role in physiological and pathophysiological processes such as inflammatory responses and neuropathic pain. Based on this, the P2Y2 has been identified as an important drug target. The specificity of current P2Y2 receptor modulators is relatively poor, and currently, specific and efficient P2Y2 receptor modulators and efficient screening strategies are lacking. In this study, a cell model based on calcium-activated chloride channels (CaCCs) was established that can detect changes in intracellular calcium concentrations and can be used to high-throughput screen for P2Y2 receptor-specific regulators. This screening strategy is suitable for screening of most G-protein-coupled receptor regulators that mediate increases in intracellular calcium signals. The cell model consists of three components that include the endogenously expressed P2Y2 receptor protein, the exogenously expressed calcium-activated chloride channel Anoctamin-1 (Ano1), and a yellow fluorescent protein mutant expressed within the cell that is highly sensitive to iodine ions. This model will allow for high-throughput screening of GPCR regulators that mediate increased intracellular calcium signaling using the calcium-activated transport of iodide ions by Ano1. We verified the ability of the model to detect intracellular calcium ion concentration using fluorescence quenching kinetic experiments by applying existing P2Y2 agonists and inhibitors to validate the screening function of the model, and we also evaluated the performance of the model in the context of high-throughput screening studies. The experimental results revealed that the model could sensitively detect intracellular calcium ion concentration changes and that the model was accurate in regard to detecting P2Y2 modulators. The resultant value of the Z-factor was 0.69, thus indicating that the model possesses good sensitivity and specificity.


Subject(s)
Calcium , High-Throughput Screening Assays , Calcium/metabolism , Calcium Signaling , Nucleotides/metabolism , Receptors, Purinergic P2Y2/genetics , Receptors, Purinergic P2Y2/metabolism
18.
Int J Forecast ; 38(2): 505-520, 2022.
Article in English | MEDLINE | ID: mdl-34276115

ABSTRACT

Hawkes processes are used in statistical modeling for event clustering and causal inference, while they also can be viewed as stochastic versions of popular compartmental models used in epidemiology. Here we show how to develop accurate models of COVID-19 transmission using Hawkes processes with spatial-temporal covariates. We model the conditional intensity of new COVID-19 cases and deaths in the U.S. at the county level, estimating the dynamic reproduction number of the virus within an EM algorithm through a regression on Google mobility indices and demographic covariates in the maximization step. We validate the approach on both short-term and long-term forecasting tasks, showing that the Hawkes process outperforms several models currently used to track the pandemic, including an ensemble approach and an SEIR-variant. We also investigate which covariates and mobility indices are most important for building forecasts of COVID-19 in the U.S.

19.
Yi Chuan ; 44(7): 556-566, 2022 Jul 20.
Article in English | MEDLINE | ID: mdl-35858768

ABSTRACT

The vascular system is responsible for the communication of information between different organs and the environment as a whole, so that it can coordinate the development of plants and respond to the changes of the environment. The signal substances moving in the vascular system are called long-distance signals. In recent years, it has been found that some long-distance molecular signals, such as microRNA, mRNA, small peptides, hormones, second messengers and proteins, can transmit extracellular stimuli from sensing tissues to target organs, so as to systematically regulate plant development process and environmental response. In this review, we summarize the molecular mechanisms of long-distance moving RNA, small peptides and proteins in plants to regulate plant organ development, nutrient uptake and stress resistance. The application potential of this field in crop breeding was discussed and prospected, in order to provide a theoretical basis for the application of genetics and breeding in crops.


Subject(s)
Plant Breeding , Plants , Peptides/metabolism , Plant Development/genetics , Plants/genetics , Plants/metabolism , Signal Transduction/physiology
20.
Opt Lett ; 46(4): 849-852, 2021 Feb 15.
Article in English | MEDLINE | ID: mdl-33577527

ABSTRACT

All-dielectric metamaterials are a promising low-loss alternative to plasmonic metamaterials for near-infrared perfect reflection, but the working bandwidth is still limited. Here we propose an ultra-wideband all-dielectric metamaterial perfect reflector that has a compact structure consisting of the subwavelength high-index grating, connection layer, and multilayer stack. Such a perfect reflector combines the advantages of quarter-wave design and resonant leaky mode, and covers an extremely wide wavelength range from 966 to 2203 nm under the normal incidence of transverse magnetic wave. By engineering the connection layer, the reflection band can be split with an ultra-narrowband tunneling of light transmission. These achievements demonstrate the promising potential of all-dielectric metamaterials as ultra-wideband reflectors for extensive applications in optical devices and systems.

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