RESUMEN

OBJECTIVE: To investigate the causal association between immune cell and different types of sepsis by using Mendelian randomization (MR) method, and to find the immune cell phenotypes causally associated with sepsis. METHODS: Summary data for various circulating immune cell phenotypes were obtained from the GWAS catalog (GCST90001391-GCST90002121). Sepsis data were sourced from the UK Biobank database. Single nucleotide polymorphisms (SNP) were used as instrumental variables. The correlation threshold of P < 5×10-6 was used to identify the strongly correlated instrumental variables, and the code was used to remove the linkage disequilibrium and the instrumental variables with F-value < 10. Inverse variance weighting (IVW) was used as the main research method to evaluate the stability and reliability of the results, including Cochran's Q test, MR-Egger regression and Leave one out. Reverse MR analysis was performed based on the immunophenotypic results of the removal of horizontal pleiotropy, and the immune cell phenotype with one-way causal association was obtained. Odds ratio (OR) and 95% confidence interval (95%CI) were used to represent the effect value of the results. RESULTS: CD16 on CD14-CD16+; monocyte had horizontal pleiotropy in sepsis (OR = 0.965 4, 95%CI was 0.933 5-0.998 3, P = 0.039 6). There were five immunophenotypes that had reverse causal associations with the types associated with sepsis. After excluding immune cell phenotypes with horizontal pleiotropy and reverse causation, a total of 42 immune cell phenotypes with sepsis, 36 immune cell phenotypes with sepsis (28-day death in critical care), 32 immune cell phenotypes with sepsis (critical care), 44 immune cell phenotypes with sepsis (28-day death), and 30 immune cell phenotypes had potential causal associations with sepsis (under 75 years old). After false discovery rate (FDR) correction, the correlations between BAFF-R on IgD- CD38br and sepsis (28-day death) were negative and strong (OR = 0.737 8, 95%CI was 0.635 9-0.856 0, P = 6.05×10-5, PFDR = 0.044 2). CONCLUSIONS: A variety of immune cell phenotypes may have a protective effect on sepsis, especially BAFF-R on IgD- CD38br expression is negatively correlated with sepsis (28-day death), which provides a new idea for immune modulation therapy in sepsis.

Asunto(s)

Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Polimorfismo de Nucleótido Simple , Sepsis , Humanos , Sepsis/genética , Fenotipo , Desequilibrio de Ligamiento , Oportunidad Relativa

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The present study investigated ion and fluoride concentrations in groundwater and their associated health risks to local populations in the southern Hebei Plain during 2018-2020. A total of 336 groundwater samples were collected from monitoring wells at 112 different locations. Statistical analysis, Gibbs diagram, principal ion ratio, and saturation index were carried out to clarify the chemical characteristics and control mechanism of groundwater. The results indicated that the groundwater types in the study area were mainly HCO3-Ca, Cl-Na, and SO4-Ca. The concentrations of cations and anions were Na+ > Ca2+ > Mg2+ > K+ and HCO3- > SO42- > Cl- > NO3- > F-, respectively. Based on the water chemical parameters, the pollution index of groundwater (PIG) was used to comprehensively evaluate the water quality. The results showed that during the study period, 60.41% of groundwater samples were suitable for drinking purposes, and 39.59% needed purification treatment to meet the requirements of drinking water standards. The groundwater quality in the western pre-hill plain areas was good, while the water quality in the northeastern and southeastern areas was poor and contaminated to varying degrees. Groundwater quality was mainly affected by the combined effect of total dissolved solids (TDS), Na+, Mg2+, Cl-, SO42- and HCO3- concentrations. Fluoride concentrations in the groundwater samples ranged from 0.07 to 8.51 mg/L, with 44% of the samples containing fluoride below the recommended limit of 0.5 mg/L, which would put the population at risk of dental caries. Also, 8% of the samples exceeded the permissible limit for fluoride in drinking water (1.5 mg/L), which would expose the local population to the risk of fluorosis. The human health risk evaluation of fluoride showed significant differences in non-carcinogenic effects between two different groups of children and adults. HIin values ranged from 0.08 to 10.19 for children and 0.03 to 4.65 for adults, with hazard indices greater than 1 at 29.16% and 10.11%, respectively. This indicates that children have a greater exposure risk than adults, and the entropy of higher risk is mainly distributed in the northeast of the study area. Based on the above analysis of the spatial evolution of groundwater chemistry, water quality, and fluoride health risks in the southern Hebei Plain region, corresponding protection and management measures were proposed, which also provided reference significance for the effective use of drinking water and health risk prevention in the region.

Asunto(s)

Caries Dental , Agua Potable , Agua Subterránea , Contaminantes Químicos del Agua , Adulto , Niño , Humanos , Fluoruros/análisis , Monitoreo del Ambiente/métodos , Agua Potable/análisis , Contaminantes Químicos del Agua/análisis , Calidad del Agua , Agua Subterránea/análisis , China

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A water-bursting evaluation of the coal seam floor is critical to ensure safety of coal mine production. The vulnerability index method based on AHP is selected for this study's evaluation method. Water pressure, measured specific yield, equivalent thickness of effective aquiclude, brittle rock thickness under mining pressure damage zone, distribution of faults, distribution of collapse column, distribution of endpoints, and the intersection of fault are taken as the evaluation index based on the analysis of geological data in the study area. The authors assessed the threat posed by the two aquifers in the lower portion of the coal seam. Separate evaluations were conducted on the Benxi and Ordovician limestone aquifers. The results' veracity was confirmed by comparing the obtained results to the water bursting point and a few boreholes. The evaluation results provide recommendations for the safe operation of coal mines.

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The bone morphogenetic protein-2 (BMP2) plays a crucial role in bone formation, growth and regeneration, which adopts a conformational wrist epitope and a linear knuckle epitope to interact with its type-I (BRI) and type-II (BRII) receptors, respectively. In this study, we systematically examine the BRII-recognition site of BMP2 at structural, energetic and dynamic levels and accurately locate hotspots of the recognition at BMP2-BRII complex interface. It is revealed that the traditional knuckle epitope (BMP2 residue range 73-92) do fully match the identified hotspots; the BMP2-recognition site includes the C-terminal region of traditional knuckle epitope as well as its flanked ß-strands. In addition, the protein context of full-length BMP2 is also responsible for the recognition by addressing conformational constraint on the native epitope segment. Therefore, we herein redefine the knuckle epitope to BMP2 residue range 84-102, which has a similar sequence length but is slid along the protein sequence by ~10 residues as compared to traditional knuckle epitope. The redefined one is also a linear epitope that is natively a double-stranded ß-sheet with two asymmetric arms as compared to the natively single ß-strand of the traditional version, although their sequences are partially overlapped to each other. It is revealed that the redefined epitope-derived peptide LN84-102 exhibits an improved affinity by >3-fold relative to the traditional epitope-derived peptide KL73-92 . Even so, the LN84-102 peptide still cannot fully represent the BMP2 recognition event by BRII that has been reported to have a nanomolar affinity. We further introduce a disulfide bond across the two arms of double-stranded ß-sheet to constrain the free LN84-102 peptide conformation, which mimics the conformational constraint addressed by protein context. Consequently, several cyclic peptides are redesigned, in which the LN84-102 (cyc89-101) is determined to exhibit a sub-micromolar affinity; this value is ~5-fold higher than its linear counterpart. Structural analysis also reveals that the cyclic peptide can interact with BRII in a similar binding mode with the redefined knuckle epitope region in full-length BMP2 protein.

Asunto(s)

Proteína Morfogenética Ósea 2/química , Epítopos/química , Péptidos/química , Cristalografía por Rayos X , Humanos , Simulación de Dinámica Molecular

RESUMEN

BACKGROUND Osteosarcoma (OS) is the most prevalent malignant primary bone tumor, resulting from severe transformation of primitive mesenchymal cells, which induces osteogenesis. Long non-coding RNA (lncRNA) MSC-AS1 triggers osteogenic differentiation by sponging microRNA (miR)-140-5p. The present study assessed the mechanism of lncRNA MSC-AS1 in OS biological features and sensitivity to cisplatin (DDP) by binding to miR-142. MATERIAL AND METHODS Firstly, lncRNA MSC-AS1 expression in OS tissues and cells was analyzed. OS cells were transfected with silenced MSC-AS1 to determine its role in OS biological behaviors, and we also assessed the effect of MSC-AS1 on OS sensitivity to DDP. Then, website prediction and dual-luciferase reporter gene assay were utilized for verification of the binding site between MSC-AS1 and miR-142. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Western blot analysis were performed to determine the effect of MSC-AS1 on expression of miR-142, cyclin-dependent kinase 6 (CDK6), and the PI3K/AKT signaling pathway. Xenograft transplantation was also applied to confirm the in vitro experiments. RESULTS Overexpressed MSC-AS1 was associated with poor prognosis of OS patients. OS cell proliferation, invasion, and migration were reduced after silencing MSC-AS1, while cell apoptosis was enhanced. Moreover, silencing MSC-AS1 made OS cells more sensitive to DDP. Interestingly, MSC-AS1 knockdown induced miR-142 expression and reduced CDK6 levels, thereby decreasing the protein expression of p-PI3K/t-PI3K and p-AKT/t-AKT. Silencing MSC-AS1 repressed OS progression in vivo. CONCLUSIONS Our study demonstrated that silencing MSC-AS1 inhibited OS biological behaviors by enhancing miR-142 to decrease CDK6 and inactivating the PI3K/AKT axis. Our results may provide new insights for OS treatment.

Asunto(s)

Antineoplásicos/farmacología , Neoplasias Óseas/genética , Resistencia a Antineoplásicos/genética , MicroARNs/metabolismo , Osteosarcoma/genética , ARN Largo no Codificante/metabolismo , Antineoplásicos/uso terapéutico , Apoptosis/genética , Neoplasias Óseas/mortalidad , Neoplasias Óseas/patología , Neoplasias Óseas/terapia , Línea Celular Tumoral , Cisplatino/farmacología , Cisplatino/uso terapéutico , Quinasa 6 Dependiente de la Ciclina/genética , Progresión de la Enfermedad , Regulación hacia Abajo , Estudios de Seguimiento , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Estimación de Kaplan-Meier , Masculino , Osteosarcoma/mortalidad , Osteosarcoma/patología , Osteosarcoma/terapia , Osteotomía , Fosfatidilinositol 3-Quinasa/metabolismo , Pronóstico , Proteínas Proto-Oncogénicas c-akt/metabolismo , ARN Largo no Codificante/genética , Transducción de Señal/genética , Ensayos Antitumor por Modelo de Xenoinjerto

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Three-dimensional topological Dirac semimetals have hitherto stimulated unprecedented research interests as a new class of quantum materials. Breaking certain types of symmetries has been proposed to enable the manipulation of Dirac fermions, and that was soon realized by external modulations such as magnetic fields. However, an intrinsic manipulation of Dirac states, which is more efficient and desirable, remains a significant challenge. Here, we report a systematic study of quasi-particle dynamics and band evolution in Cd3As2 thin films with controlled chromium (Cr) doping by both magneto-infrared spectroscopy and electrical transport. We observe the √B relation of inter-Landau-level resonance in Cd3As2, an important signature of ultrarelativistic massless state inaccessible in previous optical experiments. A crossover from quantum to quasi-classical behavior makes it possible to directly probe the mass of Dirac fermions. Importantly, Cr doping allows for a Dirac mass acquisition and topological phase transition enabling a desired dynamic control of Dirac fermions. Corroborating with the density-functional theory calculations, we show that the mass generation can be explained by the explicit C4 rotation symmetry breaking and the resultant Dirac gap engineering through Cr substitution for Cd atoms. The manipulation of the system symmetry and Dirac mass in Cd3As2 thin films provides a tuning knob to explore the exotic states stemming from the parent phase of Dirac semimetals.

RESUMEN

The progress in exploiting new electronic materials has been a major driving force in solid-state physics. As a new state of matter, a Weyl semimetal (WSM), in particular a type-II WSM, hosts Weyl fermions as emergent quasiparticles and may harbour novel electrical transport properties. Nevertheless, such a type-II WSM material has not been experimentally observed. In this work, by performing systematic magneto-transport studies on thin films of a predicted material candidate WTe2, we observe notable negative longitudinal magnetoresistance, which can be attributed to the chiral anomaly in WSM. This phenomenon also exhibits strong planar orientation dependence with the absence along the tungsten chains, consistent with the distinctive feature of a type-II WSM. By applying a gate voltage, we demonstrate that the Fermi energy can be in-situ tuned through the Weyl points via the electric field effect. Our results may open opportunities for implementing new electronic applications, such as field-effect chiral devices.

RESUMEN

BACKGROUND: This study aims to compare the efficacy and safety between zoledronic acid combined with calcium and calcium alone to prevent aromatase inhibitor-associated bone loss for postmenopausal breast cancer patients receiving adjuvant letrozole. METHODS: One hundred twenty patients were randomly divided into two groups, A and B. Patients in group A (n=60) received modified radical mastectomy or breast-conserving surgery + four cycles of AC followed by T regimen (optional) + radiotherapy (optional) + letrozole 2.5 mg daily + calcium 500 mg twice daily + vitamin D 400 international units daily +4 mg of zoledronic acid every 6 months, while patients in group B (n=60) were not given zoledronic acid and the rest of the treatments of group B were the same as group A. All the patients were followed up for 1 year. The primary endpoint was the intrapatient percentage change in lumbar spine (LS) bone mineral density (BMD) from baseline to month 12. Secondary endpoints included the percentage change in total hip (TH) and femoral neck (FN) BMD, the incidence of osteoporosis, the incidence of a clinically meaningful 5% decline in BMD at 1 year, change of serum N-telopeptide of type 1 collagen (NTX) and bone-specific alkaline phosphatase (BSAP) concentrations. RESULTS: Patients in group A had a statistically significant higher average change and average percent change in LS, FN, and TH than group B. Group A had a statistically significant lower incidence of a clinically meaningful loss of bone density at the LS, FN, or TH than Group B. The incidence of osteoporosis in group A was significantly lower than group B. The decreases in NTX and BSAP concentrations from baseline to month 12 in patients of group A were significant; in contrast, patients in group B were found to have increases in NTX and BSAP concentrations from baseline. The most common adverse reactions in patients are flu-like symptoms (38%), bone pain (28%), and joint pain (20%). CONCLUSION: AI-associated bone loss can be prevented by concurrent zoledronic acid for postmenopausal breast cancer patients.

RESUMEN

The formation of fibrocartilage, cartilaginous and bony calluses is vital for bone healing following a fracture. Fibroblasts, chondrocytes and osteoblasts are critical functional cells that are involved in these three processes, respectively. Platelet­derived growth factor (PDGF), a growth factor that is released from platelet particles and appears during the early stages at the site of fractures, is essential in bone healing via regulation of cell proliferation and differentiation. However, the effects of PDGF on the chondrocytes remain unclear. In the present study, PDGF promoted phosphorylation of Src and upregulated the expression level of G­protein­coupled receptor kinase interacting protein­1 (GIT1) according to the results of the cell culture of chondrocytes in vitro and western blotting. However, the effect of PDGF on the upregulation of GIT1 expression was mostly inhibited by the Src inhibitor, PP2. After knocking down GIT1 expression using siRNA, the phosphorylation of Src continued to be induced by PDGF, although the expression of GIT1 was inhibited. Furthermore, the results indicated that PDGF promoted chondrocyte proliferation and migration, however, the effect on cell apoptosis induction was suppressed after adding the Src inhibitor, PP2. Additionally, when knocking down GIT1 using siRNA, the expression level of GIT1 decreased, which is similar to the effect of the Src inhibitor, PP2. The current study demonstrates that PDGF may initially activate the phosphorylation of Src, and subsequently induce GIT1 expression to promote chondrocyte proliferation and migration, but suppress cell apoptosis.

Asunto(s)

Proteínas de Ciclo Celular/genética , Condrocitos/efectos de los fármacos , Condrocitos/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Fosfoproteínas/genética , Factor de Crecimiento Derivado de Plaquetas/farmacología , Animales , Apoptosis/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Fosforilación , Ratas , Familia-src Quinasas/metabolismo

RESUMEN

Chondrocytes play a critical role in the repair process of osteoarthritis, which is also known as degenerative arthritis. Integrins, as the key family of cell surface receptors, are responsible for the regulation of chondrocyte proliferation, differentiation, survival and apoptosis through the recruitment and activation of downstream adaptor proteins. Moreover, G-protein-coupled receptor kinase interacting protein-1 (GIT1) exerts its effects on cell proliferation and migration through interaction with various cytokines. It has been previously suggested that GIT1 acts as a vital protein downstream of the integrin-mediated pathway. In the present study, we investigated the effects of integrin-ß1 on cell proliferation and apoptosis, as well as the underlying mechanisms in chondrocytes in vitro. Following transfection with a vector expressing integrin-ß1, our results revealed that the overexpression of integrin-ß1 enhanced GIT1 expression, whereas the knockdown of integrin-ß1 by siRNA suppressed GIT1 expression. However, no significant effect was observed on integrin-ß1 expression following the enforced overexpression of GIT1, which suggests that GIT1 is localized downstream of integrin-ß1. In other words, integrin-ß1 regulates the expression of GIT1. Furthermore, this study demonstrated that integrin-ß1 and GIT1 increased the expression levels of aggrecan and type II collagen, thus promoting chondrocyte proliferation; however, they inhibited chondrocyte apoptosis. Taken together, our data demonstrate that integrin-ß1 plays a vital role in chondrocyte proliferation, differentiation and apoptosis. GIT1 exerts effects similar to those of integrin-ß1 and is a downstream target of integrin-ß1.

Asunto(s)

Apoptosis/genética , Proteínas de Ciclo Celular/genética , Condrocitos/metabolismo , Regulación de la Expresión Génica , Integrina beta1/metabolismo , Fosfoproteínas/genética , Animales , Proliferación Celular , Matriz Extracelular/metabolismo , Ratas