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Porcine respiratory and reproductive syndrome (PRRS) is one of the most devastating infectious diseases of pigs, causing reproductive failures in sows and severe respiratory symptoms in piglets and growing pigs. MicroRNAs (miRNAs) are reported to play an essential role in virus-host interactions. In this study, we demonstrated that miR-451 enhanced type I interferon (IFN-I) production through targeting proteasome subunit ß8 (PSMB8), therefore restricting PRRS virus (PRRSV) replication. We showed that the expression of PSMB8 was upregulated by PRRSV infection, and knockdown of PSMB8 inhibited PRRSV replication by promoting IFN-I production. Moreover, we demonstrated that PSMB8 interacted with the regulatory domain of IRF3 to mediate K48-linked polyubiquitination and degradation of IRF3. Also, importantly, we showed that PSMB8, as a target gene of miR-451, negatively regulated IFN-I production by promoting IRF3 degradation, which is a previously unknown mechanism for PSMB8 to modulate innate immune responses. IMPORTANCE: Porcine respiratory and reproductive syndrome virus (PRRSV), as a huge threat to the swine industry, is a causative agent that urgently needs to be solved. The dissecting of PRRSV pathogenesis and understanding of the host-pathogen interaction will provide insights into developing effective anti-PRRSV strategies. In this study, we showed that miR-451 dramatically inhibited PRRSV replication by targeting proteasome subunit ß8 (PSMB8), a subunit of the immunoproteasome. Mutation of PSMB8 is often related to autoinflammatory diseases due to the elevated IFN production. We revealed that PSMB8 downregulated IFN production by promoting IRF3 degradation. In addition, we showed that PRRSV infection upregulated PSMB8 expression. Taken together, our findings reveal that miR-451 is a negative regulator of PRRSV replication, and PSMB8, a target gene of miR-451, negatively regulates IFN-I production by promoting IRF3 degradation, which is a previously unknown mechanism for PSMB8 to regulate innate immune responses.
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Subseasonal rainfall forecast skill is critical to support preparedness for hydrometeorological extremes. We assess how a process-informed evaluation, which subsamples forecasting model members based on their ability to represent potential predictors of rainfall, can improve monthly rainfall forecasts within Central America in the following month, using Costa Rica and Guatemala as test cases. We generate a constrained ensemble mean by subsampling 130 members from five dynamic forecasting models in the C3S multimodel ensemble based on their representation of both (a) zonal wind direction and (b) Pacific and Atlantic sea surface temperatures (SSTs), at the time of initialization. Our results show in multiple months and locations increased mean squared error skill by 0.4 and improved detection rates of rainfall extremes. This method is transferrable to other regions driven by slowly-changing processes. Process-informed subsampling is successful because it identifies members that fail to represent the entire rainfall distribution when wind/SST error increases.
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The optimal method for administering meropenem remains controversial. This study was conducted to explore the optimal two-step infusion strategy (TIT), and to investigate whether TIT is superior to intermittent infusion therapy (IIT) and prolonged infusion therapy (PIT). A physiologically based pharmacokinetics model for critically ill patients was established and evaluated. The validated model was utilized to evaluate the pharmacokinetics/pharmacodynamics (PK/PD) target attainment of meropenem. The PK/PD target attainment of different TITs varied greatly, and the total infusion duration and the first-step dose greatly affected these values. The optimal TIT was 0.25 g (30 min) + 0.75 g (150 min) at MICs of ≤2 mg/L, and 0.25 g (45 min) + 0.75 g (255 min) at MICs of 4-8 mg/L. The PK/PD target attainment of optimal TIT, PIT, and IIT were 100 % at MICs of ≤1 mg/L. When MIC increased to 2-8 mg/L, the PK/PD target attainment of optimal TIT was similar to that of PIT and higher than IIT. In conclusion, TIT did not significantly improve the PK/PD target attainment of meropenem compared with PIT. IIT is adequate at MICs of ≤1 mg/L, and PIT may be the optimal meropenem infusion method in critically ill patients with MICs of 2-8 mg/L.
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Antibacterianos , Estado Terminal , Meropeném , Testes de Sensibilidade Microbiana , Meropeném/farmacocinética , Meropeném/administração & dosagem , Meropeném/farmacologia , Humanos , Antibacterianos/farmacocinética , Antibacterianos/administração & dosagem , Antibacterianos/farmacologia , Infusões Intravenosas , Masculino , Modelos Biológicos , Pessoa de Meia-Idade , Feminino , IdosoRESUMO
Mutations in amino acid sequences can provoke changes in protein function. Accurate and unsupervised prediction of mutation effects is critical in biotechnology and biomedicine, but remains a fundamental challenge. To resolve this challenge, here we present Protein Mutational Effect Predictor (ProMEP), a general and multiple sequence alignment-free method that enables zero-shot prediction of mutation effects. A multimodal deep representation learning model embedded in ProMEP was developed to comprehensively learn both sequence and structure contexts from ~160 million proteins. ProMEP achieves state-of-the-art performance in mutational effect prediction and accomplishes a tremendous improvement in speed, enabling efficient and intelligent protein engineering. Specifically, ProMEP accurately forecasts mutational consequences on the gene-editing enzymes TnpB and TadA, and successfully guides the development of high-performance gene-editing tools with their engineered variants. The gene-editing efficiency of a 5-site mutant of TnpB reaches up to 74.04% (vs 24.66% for the wild type); and the base editing tool developed on the basis of a TadA 15-site mutant (in addition to the A106V/D108N double mutation that renders deoxyadenosine deaminase activity to TadA) exhibits an A-to-G conversion frequency of up to 77.27% (vs 69.80% for ABE8e, a previous TadA-based adenine base editor) with significantly reduced bystander and off-target effects compared to ABE8e. ProMEP not only showcases superior performance in predicting mutational effects on proteins but also demonstrates a great capability to guide protein engineering. Therefore, ProMEP enables efficient exploration of the gigantic protein space and facilitates practical design of proteins, thereby advancing studies in biomedicine and synthetic biology.
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Aprendizado Profundo , Edição de Genes , Mutação , Engenharia de Proteínas , Engenharia de Proteínas/métodos , Edição de Genes/métodos , HumanosRESUMO
Background: Limited evidence exists regarding the clinical baseline characteristics at admission for acute kidney injury (AKI) before and after interventional cardiac procedures (ICP) in elderly patients with coronary artery disease (CAD). Methods: A total of 488 elderly patients were enrolled in this retrospective single-center study conducted from January 2019 to July 2022, and a classification and regression tree (CART) analysis was performed to identify the high-risk population. Results: The AKI incidence was 21.1 % (103/488) in this study, with 27 and 76 individuals developing AKI before and after ICP, respectively. CART analysis revealed that exposure to nephrotoxic drugs and diuretics had the strongest predictive capacities for identifying patients at risk of developing pre-ICP AKI, with the incidence among these high-risk patients ranging from 6.5 % to 13.8 %. Meanwhile, the optimum discriminators for identifying those at high risk of post-ICP AKI were the administration of diuretics, D-value ≤ -860 mL, age >73 years, and administration of nephrotoxic drugs, and the latter model predicted that the AKI incidence among high-risk patients was between 50.0 % and 60.0 %. Conclusions: Elderly patients with CAD exhibited an elevated incidence of AKI. CART models suggested that exposure to nephrotoxic drugs and diuretics, D-value, and age were significantly associated with AKI in the elderly with CAD. Importantly, these baseline characteristics at admission could be utilized to identify elderly patients at high risk of pre- and post-ICP AKI.
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PURPOSE: Numerous epidemiological studies have suggested a possible association between dysphagia and the risk of decline in Activities of daily living (ADL) among older adults. This systematic review and meta-analysis aimed to elucidate the relationship between dysphagia and ADL in older adults. METHODS: PubMed, Web of Science, Cochrane Library, Embase, Ebsco, MEDLINE, Wiley, CINAHL, and Ovid databases were comprehensively examined for relevant studies published up to October 31, 2022. Quantitative studies published in English were included to explore the relationship between dysphagia and ADL in people aged 65 years and older. The NIH Quality Assessment Tool was used to assess the study quality. R software was used to draw forest plots and I2 was employed to indicate study heterogeneity. Sensitivity analysis was performed using the one-by-one exclusion method. Publication bias was measured using funnel plots and Egger's test. RESULTS: A total of 3,498 studies were retrieved from the database, 22 of which were eventually included in the systematic evaluation, and 14 of which were subjected to meta-analysis. Data from nine studies were categorical variables, and meta-analysis results showed that swallowing disorders in older adults were associated with a lower ability to perform ADL (OR = 3.39, 95% CI: 2.55-4.50, p < 0.001), with moderate heterogeneity (I2 = 62%, p = 0.006). Data from seven studies were continuous variables, resulting in a negative association between the prevalence of dysphagia and ADLs in older adults (SMD = -0.80, 95% CI: -1.08 to -0.51, p < 0.001), with high heterogeneity (I2 = 94%, p < 0.001). Sensitivity analysis showed robust results, funnel plots and Egger's test indicated no publication bias. CONCLUSION: Dysphagia is significantly associated with the capacity to perform ADL. Prevention and screening of dysphagia in older patients dependent on others for daily care are needed. Further long-term studies are needed in the future to prove causality.
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Emulsified meat products contain high animal fat content, and excessive intake of animal fat is not good for health, so people are paying more and more attention to reduced-fat meat products. This study investigated the impact of varying proportions of pork back-fat and/or resistant starch on the proximate composition, water and fat retention, texture properties, color, and rheology characteristic of pork batter. The results found that replacing pork back-fat with resistant starch and ice water significantly decreased the total lipid and energy contents of cooked pork batter (p < 0.05) while improving emulsion stability, cooking yield, texture, and rheology properties. Additionally, when the pork back-fat replacement ratio was no more than 50%, there was a significant increase in emulsion stability, cooking yield, hardiness, springiness, cohesiveness, chewiness, and L* and G' values (p < 0.05). Furthermore, resistant starch and ice water enhanced myosin head and tail thermal stability and increased G' value at 80 °C. However, the initial relaxation times significantly decreased (p < 0.05) and the peak ratio of P21 significantly increased from 84.62% to 94.03%, suggesting reduced fluidity of water. In conclusion, it is feasible to use resistant starch and ice water as a substitute for pork back-fat in order to produce reduced-fat pork batter with favorable gel and rheology properties.
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Persistent and intense uterine contraction is a risk factor for preterm labor. We previously found that methyl-CpG-binding protein 2 (MeCP2), as a target of infection-related microRNA miR-212-3p, may play an inhibitory role in regulating myometrium contraction. However, the molecular mechanisms by which MeCP2 regulates myometrial contraction are still unknown. In this study, we found that MeCP2 protein expression was lower in myometrial specimens obtained from preterm labor cases, compared to those obtained from term labor cases. Herein, using RNA sequence analysis of global gene expression in human uterine smooth muscle cells (HUSMCs) following siMeCP2, we show that MeCP2 silencing caused dysregulation of the cholesterol metabolism pathway. Notably, MeCP2 silencing resulted in the upregulation of CYP27A1, the key enzyme involved in regulating cholesterol homeostasis, in HUSMCs. Methylation-specific PCR, chromatin immunoprecipitation, and dual luciferase reporter gene technology indicated that MeCP2 could bind to the methylated CYP27A1 promoter region and repress its transcription. Administration of siCYP27A1 in a lipopolysaccharide (LPS)-induced preterm labor mouse model delayed the onset of preterm labor. Human preterm myometrium and the LPS-induced preterm labor mouse model both showed lower expression of MeCP2 and increased expression of CYP27A1. These results demonstrated that aberrant upregulation of CYP27A1 induced by MeCP2 silencing is one of the mechanisms facilitating inappropriate myometrial contraction. CYP27A1 could be exploited as a novel therapeutic target for preterm birth.
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Proteína 2 de Ligação a Metil-CpG , Miométrio , Trabalho de Parto Prematuro , Contração Uterina , Adulto , Animais , Feminino , Humanos , Camundongos , Gravidez , Colestanotriol 26-Mono-Oxigenase/genética , Colestanotriol 26-Mono-Oxigenase/metabolismo , Colesterol/metabolismo , Lipopolissacarídeos/farmacologia , Proteína 2 de Ligação a Metil-CpG/metabolismo , Proteína 2 de Ligação a Metil-CpG/genética , Miócitos de Músculo Liso/metabolismo , Miométrio/metabolismo , Trabalho de Parto Prematuro/metabolismo , Trabalho de Parto Prematuro/genética , Regiões Promotoras Genéticas , Contração Uterina/efeitos dos fármacosRESUMO
A novel composite hydrogel was synthesized via Schiff base reaction between chitosan and di-functional poly(ethylene glycol) (DF-PEG), incorporating glucose oxidase (GOx) and cobalt metal-organic frameworks (Co-MOF). The resulting CS/PEG/GOx@Co-MOF composite hydrogel was characterized using Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS), thermogravimetric analysis (TGA), and energy-dispersive X-ray spectroscopy (EDS). The results confirmed successful integration and uniform distribution of Co-MOF within the hydrogel matrix. Functionally, the hydrogel exploits the catalytic decomposition of glucose by GOx to generate gluconic acid and hydrogen peroxide (H2O2), while Co-MOF gradually releases metal ions and protects GOx. This synergy enhanced the antibacterial activity of the composite hydrogel against both Gram-positive (S. aureus) and Gram-negative bacteria (E. coli), outperforming conventional chitosan-based hydrogels. The potential of the composite hydrogel in treating wound infections was evaluated through antibacterial and wound healing experiments. Overall, CS/PEG/GOx@Co-MOF hydrogel holds great promise for the treatment of wound infections, paving the way for further research and potential clinical applications.
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Antibacterianos , Quitosana , Escherichia coli , Hidrogéis , Estruturas Metalorgânicas , Staphylococcus aureus , Cicatrização , Quitosana/química , Quitosana/farmacologia , Antibacterianos/farmacologia , Antibacterianos/química , Estruturas Metalorgânicas/química , Estruturas Metalorgânicas/farmacologia , Cicatrização/efeitos dos fármacos , Hidrogéis/química , Hidrogéis/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Glucose Oxidase/química , Animais , Cobalto/química , Polietilenoglicóis/química , Testes de Sensibilidade MicrobianaRESUMO
Depression is a prevalent psychological condition with limited treatment options. While its etiology is multifactorial, both chronic stress and changes in microbiome composition are associated with disease pathology. Stress is known to induce microbiome dysbiosis, defined here as a change in microbial composition associated with a pathological condition. This state of dysbiosis is known to feedback on depressive symptoms. While studies have demonstrated that targeted restoration of the microbiome can alleviate depressive-like symptoms in mice, translating these findings to human patients has proven challenging due to the complexity of the human microbiome. As such, there is an urgent need to identify factors upstream of microbial dysbiosis. Here we investigate the role of mucin 13 as an upstream mediator of microbiome composition changes in the context of stress. Using a model of chronic stress, we show that the glycocalyx protein, mucin 13, is selectively reduced after psychological stress exposure. We further demonstrate that the reduction of Muc13 is mediated by the Hnf4 transcription factor family. Finally, we determine that deleting Muc13 is sufficient to drive microbiome shifts and despair behaviors. These findings shed light on the mechanisms behind stress-induced microbial changes and reveal a novel regulator of mucin 13 expression.
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Depressão , Disbiose , Microbioma Gastrointestinal , Estresse Psicológico , Animais , Masculino , Camundongos , Comportamento Animal/fisiologia , Depressão/metabolismo , Depressão/microbiologia , Disbiose/metabolismo , Disbiose/microbiologia , Microbioma Gastrointestinal/fisiologia , Fator 4 Nuclear de Hepatócito/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mucinas/metabolismo , Estresse Psicológico/metabolismo , Estresse Psicológico/microbiologiaRESUMO
Chemo-immunotherapy combinations have been regarded as one of the most practical ways to improve immunotherapy response in cancer patients. In this study, we integrate the transcriptomics data from anti-PD-1-treated tumors and compound-treated cancer cell lines to systematically screen for chemo-immunotherapy synergisms in silico. Through analyzing anti-PD-1 induced expression changes in patient tumors, we develop a shift ability score to measure if a chemotherapy or a small molecule inhibitor treatment can shift anti-PD-1 resistance in tumor cells. By applying shift ability analysis to 41,321 compounds and 16,853 shRNA treated cancer cell lines transcriptomic data, we characterize the landscape of chemo-immunotherapy synergism and experimentally validated a mitochondrial RNA-dependent mechanism for drug-induced immune activation in tumor. Our study represents an effort to mechanistically characterize chemo-immunotherapy synergism and will facilitate future pre-clinical and clinical studies.
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Imunoterapia , Neoplasias , Humanos , Quimioterapia Combinada , Linhagem Celular , Perfilação da Expressão Gênica , Neoplasias/tratamento farmacológico , Neoplasias/genéticaRESUMO
BACKGROUND: Cardiovascular patients experience high rates of adverse outcomes following discharge from hospital, which may be preventable through early identification and targeted action. This study aimed to investigate the effectiveness and explainability of machine learning algorithms in predicting unplanned readmission and death in cardiovascular patients at 30 days and 180 days from discharge. METHODS: Gradient boosting machines were trained and evaluated using data from hospital electronic medical records linked to hospital administrative and mortality data for 39,255 patients admitted to four hospitals in New South Wales, Australia between 2017 and 2021. Sociodemographic variables, admission history, and clinical information were used as potential predictors. The performance was compared to LASSO regression, as well as the HOSPITAL and LACE risk score indices. Important risk factors identified by the gradient-boosting machine model were explored using Shapley values. RESULTS: The models performed well, especially for the mortality outcomes. Area under the receiver operating characteristic curve values were 0.70 for readmission and 0.87-0.90 for mortality using the full gradient boosting machine algorithms. Among the top predictors for 30-day and 180-day readmission were increased red cell distribution width, old age (especially above 80 years), high measured troponin and urea levels, not being married or in a relationship, and low albumin levels. For mortality, these included increased red cell distribution width, old age (especially older than 70 years), high measured troponin and urea levels, high neutrophil and monocyte counts, and low eosinophil and lymphocyte counts. The Shapley values gave clear insight into the dynamics of decision-tree-based models. CONCLUSIONS: We demonstrated an explainable predictive algorithm to identify cardiovascular patients who are at high risk of readmission or death at discharge from the hospital and identified key risk factors.
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Doenças Cardiovasculares , Aprendizado de Máquina , Readmissão do Paciente , Humanos , Readmissão do Paciente/estatística & dados numéricos , Masculino , Feminino , Idoso , Doenças Cardiovasculares/mortalidade , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , Fatores de Risco , New South Wales/epidemiologia , Algoritmos , AdultoRESUMO
The synthesis of group 4 metal 1-metallacyclobuta-2,3-dienes as organometallic analogues of elusive 1,2-cyclobutadiene has so far been limited to SiMe3 substituted examples. We present the synthesis of two Ph substituted dilithiated ligand precursors for the preparation of four new 1-metallacyclobuta-2,3-dienes [rac-(ebthi)M] (M=Ti, Zr; ebthi=1,2-ethylene-1,10-bis(η5-tetrahydroindenyl)). The organolithium compounds [Li2(RC3Ph)] (1 b: R=Ph, 1 c: R=SiMe3) as well as the metallacycles of the general formula [rac-(ebthi)M(R1C3R2)] (2 b: M=Ti, R1=R2=Ph, 2 c: M=Ti, R1=Ph, R2=SiMe3; 3 b: M=Zr, R1=R2=Ph; 3 c: M=Zr, R1=Ph, R2=SiMe3) were fully characterised. Single crystal X-ray diffraction and quantum chemical bond analysis of the Ti and Zr complexes reveal ligand influence on the biradicaloid character of the titanocene complexes. X-band EPR spectroscopy of structurally similar Ti complexes [rac-(ebthi)Ti(Me3SiC3SiMe3)] (2 a), 2 b, and 2 c was carried out to evaluate the accessibility of an EPR active triplet state. Cyclic voltammetry shows that introduction of Ph groups renders the complexes easier to reduce. 13C CPMAS NMR analysis provides insights into the cause of the low field shift of the resonances of metal-bonded carbon atoms and provides evidence of the absence of the ß-C-Ti interaction.
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Ascorbic acid (AA), which plays a vital role in the metabolism of the human body, is closely correlated with various diseases, including rheumatoid arthritis, scurvy, Parkinson's disease, urinary stones, and diarrhea. The detection of AA is of great significance for early prevention and diagnosis of related diseases. In this paper, a high-performance photoelectrochemical (PEC) sensor was constructed based on cadmium sulfide-gold (CdS-Au) composite nanomaterials for ultrasensitive ascorbic acid (AA) detection. Due to the localized surface plasmon resonance (LSPR) effect of gold nanoparticles (AuNPs), the PEC performance of CdS-Au composite nanomaterials was significantly improved compared to CdS semiconductor nanomaterials. Under the optimal conditions, the AA concentration was linearly related to the photocurrent signal in the range of 0.01 µM-200 µM, with the detection limit being 0.2 nM (S/N = 3) and the sensitivity being 642.9 µA mM-1 cm-2. In addition, the mechanism of the PEC sensor based on CdS-Au composite nanomaterials for ultrasensitive AA detection was discussed. Lastly, the self-constructed PEC sensors have been successfully applied in detecting AA in vitamin C tablets and actual blood samples, meeting the detection criteria required by the Chinese Pharmacopoeia (CP, 2020 edition). The self-fabricated PEC sensors in this paper are expected to be used for quality assessment of AA-related drugs and diagnosis of relevant diseases.
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Nanopartículas Metálicas , Nanoestruturas , Humanos , Ressonância de Plasmônio de Superfície , Ouro , Ácido AscórbicoRESUMO
OBJECTIVES: Agriculture is the one of the hazardous industries in the world. Though there is significant investment in agricultural safety, machine injuries continue to be the leading cause of agriculture injuries worldwide. The objective of this study was to provide a comprehensive literature review on global patterns in agricultural machine injuries and establish a framework for future research aimed at addressing safety concerns in the agriculture sector. METHODS: The existing scholarship on farm machine injuries can be categorized into three main areas: a) farming machine/equipment injuries, b) factors associated with these injuries, and c) injury patterns. RESULTS: Overall, the findings highlight that farm tractors are the primary source of injuries for both fatal and non-fatal incidents regardless of region. Other common sources of injuries were harvesting machinery and hand/power tools in Asia, ATVs in North America and woodworking machinery in Europe. Inadequate training in operating farm equipment was reported as the most likely factor contributing to machine-related injuries. Lastly, the patterns of injuries vary based on the interaction between humans and machinery. For instance, rollovers often result in severe head and fracture injuries, while thresher incidents can lead to amputation of hands, arms, and other body parts. CONCLUSION: Addressing these injuries by implementing safety protocols will not only enhance the well-being of farm workers but potentially attract more workers to the sector, which is currently experiencing labor shortages due to machine-related injuries.
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Fraturas Ósseas , Ferimentos e Lesões , Humanos , Acidentes de Trabalho , Agricultura , Fazendeiros , Fazendas , Ferimentos e Lesões/epidemiologiaRESUMO
The ability to utilize dissolved organic phosphorus (DOP) gives phytoplankton competitive advantages in P-limited environments. Our previous research indicates that the diatom Phaeodactylum tricornutum could grow on glyphosate, a DOP with carbon-phosphorus (C-P) bond and an herbicide, as sole P source. However, direct evidence and mechanism of glyphosate utilization are still lacking. In this study, using physiological and isotopic analysis, combined with transcriptomic profiling, we demonstrated the uptake of glyphosate by P. tricornutum and revealed the candidate responsible genes. Our data showed a low efficiency of glyphosate utilization by P. tricornutum, suggesting that glyphosate utilization costs energy and that the alga possessed an herbicide-resistant type of 5-enolpyruvylshikimate-3-phosphate (EPSP) synthase. Compared to the P-limited cultures, the glyphosate-grown P. tricornutum cells up-regulated genes involved in DNA replication, cell growth, transcription, translation, carbon metabolism, and many genes encoding antioxidants. Additionally, cellular C and silicon (Si) increased remarkably while cellular nitrogen (N) declined in the glyphosate-grown P. tricornutum, leading to higher Si:C and Si:N ratios, which corresponded to the up-regulation of genes involved in the C metabolism and Si uptake and the down-regulation of those encoding N uptake. This has the potential to enhance C and Si export to the deep sea when P is limited but phosphonate is available. In sum, our study documented how P. tricornutum could utilize the herbicide glyphosate as P nutrient and how glyphosate utilization may affect the element content and stoichiometry in this diatom, which have important ecological implications in the future ocean.IMPORTANCEGlyphosate is the most widely used herbicide in the world and could be utilized as phosphorus (P) source by some bacteria. Our study first revealed that glyphosate could be transported into Phaeodactylum tricornutum cells for utilization and identified putative genes responsible for glyphosate uptake. This uncovers an alternative strategy of phytoplankton to cope with P deficiency considering phosphonate accounts for about 25% of the total dissolved organic phosphorus (DOP) in the ocean. Additionally, accumulation of carbon (C) and silicon (Si), as well as elevation of Si:C ratio in P. tricornutum cells when grown on glyphosate indicates glyphosate as the source of P nutrient has the potential to result in more C and Si export into the deep ocean. This, along with the differential ability to utilize glyphosate among different species, glyphosate supply in dissolved inorganic phosphorus (DIP)-depleted ecosystems may cause changes in phytoplankton community structure. These insights have implications in evaluating the effects of human activities (use of Roundup) and climate change (potentially reducing DIP supply in sunlit layer) on phytoplankton in the future ocean.
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Diatomáceas , Herbicidas , Organofosfonatos , Humanos , Glifosato , Silício/metabolismo , Fósforo/metabolismo , Matéria Orgânica Dissolvida , Ecossistema , Fitoplâncton/metabolismo , Herbicidas/metabolismo , Carbono/metabolismo , Organofosfonatos/metabolismoRESUMO
Somatostatin analogues (SSTA) are first-line pharmacological treatment choice for acromegaly, which received satisfying tumor shrinkage and normalization of growth hormone. However, there are still patients unresponsive to SSTA, and the underline mechanism remains unknown. Besides, there is no evidence regarding the role of endoplasmic reticulum stress (ERS) and its transmission in SSTA resistance, which also require investigation. Primary growth hormone adenoma cells and cell lines were treated with SSTA; autophagy double-labeled LC3 (mRFP-GFP) adenovirus transfection, flow cytometry sorting, western blotting, calcium imaging as well as immunofluorescence staining were used to determine ERS and autophagy signal transmission; xenograft and syngeneic tumor in vivo model were exploited to confirm the ERS signal transmission mediated effect. Our results revealed that SSTA induces ERS in pituitary growth hormone (GH) adenoma cells. The ERS signals can be intercellularly transmitted, leading to less responsible to SSTA treatment. Moreover, SSTA stimulates inositol triphosphate (IP3) elevation, mediating ERS intercellular transfer. In addition, connexin 36 tunnels ERS transmission, and its blocker, Quinine, exhibits a synergistic effect with SSTA treating GH adenoma. Our study provided insight into ERS intercellular transmission mediated SSTA resistance, which could be translated into clinical usage to improve SSTA efficiency in GH adenoma treatment.
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Adenoma , Neoplasias Hipofisárias , Humanos , Somatostatina/farmacologia , Somatostatina/uso terapêutico , Hormônio do Crescimento/metabolismo , Hormônio do Crescimento/uso terapêutico , Neoplasias Hipofisárias/tratamento farmacológico , Neoplasias Hipofisárias/genética , Neoplasias Hipofisárias/metabolismo , Proteína delta-2 de Junções Comunicantes , Adenoma/tratamento farmacológico , Estresse do Retículo EndoplasmáticoRESUMO
INTRODUCTION: Agricultural injuries remain a major concern in North America, with a fatal injury rate of 19.5 deaths per 100,000 workers in the United States. Numerous research efforts have sought to compile and analyze records of agricultural-related injuries and fatalities at a national level, utilizing resources, ranging from newspaper clippings and hospital records to Emergency Medical System (EMS) data, death certifications, surveys, and other multiple sources. Despite these extensive efforts, a comprehensive understanding of injury trends over extended time periods and across diverse types of data sources remains elusive, primarily due to the duration of data collection and the focus on specific subsets. METHODS: This systematic review, following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, consolidates and analyzes agricultural injury surveillance data from 48 eligible papers published between 1985 and 2022 to offer a holistic understanding of trends and challenges. RESULTS: These papers, reporting an average of 25,000 injuries each, were analyzed by database source type, injury severity, nature of injury, body part, source of injury, event/exposure, and age. One key finding is that the top source of injury or event/exposure depends on the chosen surveillance system and injury severity, underscoring the need of diverse data sources for a nuanced understanding of agricultural injuries. CONCLUSION: This study provides policymakers, researchers, and practitioners with crucial insights to bolster the development and analysis of surveillance systems in agricultural safety. The overarching aim is to address the pressing issue of agricultural injuries, contributing to a safer work environment and ultimately enhancing the overall well-being of individuals engaged in agriculture.
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Acidentes de Trabalho , Ferimentos e Lesões , Humanos , Estados Unidos/epidemiologia , Agricultura , Canadá/epidemiologia , América do Norte , Ferimentos e Lesões/epidemiologiaRESUMO
BACKGROUND: Approximately 35% of pituitary adenoma (PA) display an aggressive profile, resulting in low surgical total resection rates, high recurrence rates, and worse prognosis. However, the molecular mechanism of PA invasion remains poorly understood. Although "a disintegrin and metalloproteinases" (ADAMs) are associated with the progression of many tumors, there are no reports on ADAM22 in PA. METHODS: PA transcriptomics databases and clinical specimens were used to analyze the expression of ADAM22. PA cell lines overexpressing wild-type ADAM22, the point mutation ADAM22, the mutated ADAM22 without disintegrin domain, and knocking down ADAM22 were generated. Cell proliferation/invasion assays, flow cytometry, immunohistochemistry, immunofluorescence, co-immunoprecipitation, mass spectrometry, Reverse transcription-quantitative real-time PCR, phos-tag SDS-PAGE, and Western blot were performed for function and mechanism research. Nude mice xenograft models and rat prolactinoma orthotopic models were used to validate in vitro findings. RESULTS: ADAM22 was significantly overexpressed in PA and could promote the proliferation, migration, and invasion of PA cells. ADAM22 interacted with integrin ß1 (ITGB1) and activated FAK/PI3K and FAK/ERK signaling pathways through its disintegrin domain to promote PA progression. ADAM22 was phosphorylated by PKA and recruited 14-3-3, thereby delaying its degradation. ITGB1-targeted inhibitor (anti-itgb1) exerted antitumor effects and synergistic effects in combination with somatostatin analogs or dopamine agonists in treating PA. CONCLUSIONS: ADAM22 was upregulated in PA and was able to promote PA proliferation, migration, and invasion by activating ITGB1 signaling. PKA may regulate the degradation of ADAM22 through post-transcriptional modification levels. ITGB1 may be a potential therapeutic target for PA.
Assuntos
Desintegrinas , Neoplasias Hipofisárias , Camundongos , Humanos , Animais , Ratos , Integrina beta1/metabolismo , Camundongos Nus , Metaloproteases , Linhagem Celular Tumoral , Movimento Celular , Proliferação de CélulasRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Echinacea purpurea (L.) Moench (EP) is a perennial herbaceous flowering plant with immunomodulatory effects. However, the immunomodulatory effects of EP on broilers after vaccination are still unclear. AIM OF THE STUDY: The aim is to study the effect of EP and Echinacea purpurea (L.) Moench extracts(EE) on avian influenza virus (AIV) immunity, and further explore the potential mechanism of immune regulation. MATERIALS AND METHODS: Broilers were fed with feed additives containing 2% EP or 0.5% EE, and vaccinated against avian influenza. The samples were collected on the 7th, 21st, and 35th day after vaccination, and the feed conversion ratio (FCR) was calculated. Blood antibody titer, jejunal sIgA content, tight junction protein, gene and protein expression of TLR4-MAPK signaling pathway were also detected. RESULTS: The results showed that vaccination could cause immune stress, weight loss, increase sIgA content, and up-regulate the expression of tight junction proteins, including zonula occludens-1 (ZO-1), Occludin, and Claudin-1, as well as the genes of Toll-like receptor 4 (TLR4), myeloid differentiation primary response 88 (MyD88), receptor-associated factor 6 (TRAF6), activator protein 1 (AP-1) protein gene expression on TLR4-mitogen-activated protein kinase (MAPK) signaling pathway, and the protein expression of MyD88, extracellular regulated protein kinases (ERK), and c-Jun N-terminal kinase (JNK). EP and EE could increase the body weight of broilers, further improve antibody titers, decrease FCR, increase sIgA levels, up-regulate the expression of tight junction proteins, including ZO-1, Occludin, and Claudin-1, as well as the genes of TLR4, MyD88, TRAF6, and AP-1 and the protein expression of MyD88, ERK, and JNK in the TLR4-MAPK signaling pathway. CONCLUSION: In conclusion, EP and EE can increase the broiler's production performance and improve vaccine immune effect through the TLR4-MAPK signaling pathway.