RESUMO

DNA damage that obstructs the replication machinery poses a significant threat to genome stability. Replication-coupled repair mechanisms safeguard stalled replication forks by coordinating proteins involved in the DNA damage response (DDR) and replication. SLF1 (SMC5-SMC6 complex localization factor 1) is crucial for facilitating the recruitment of the SMC5/6 complex to damage sites through interactions with SLF2, RAD18, and nucleosomes. However, the structural mechanisms of SLF1's interactions are unclear. In this study, we determined the crystal structure of SLF1's ankyrin repeat domain bound to an unmethylated histone H4 tail, illustrating how SLF1 reads nascent nucleosomes. Using structure-based mutagenesis, we confirmed a phosphorylation-dependent interaction necessary for a stable complex between SLF1's tandem BRCA1 C-Terminal domain (tBRCT) and the phosphorylated C-terminal region (S442 and S444) of RAD18. We validated a functional role of conserved phosphate-binding residues in SLF1, and hydrophobic residues in RAD18 that are adjacent to phosphorylation sites, both of which contribute to the strong interaction. Interestingly, we discovered a DNA-binding property of this RAD18-binding interface, providing an additional domain of SLF1 to enhance binding to nucleosomes. Our results provide critical structural insights into SLF1's interactions with post-replicative chromatin and phosphorylation-dependent DDR signalling, enhancing our understanding of SMC5/6 recruitment and/or activity during replication-coupled DNA repair.

RESUMO

BACKGROUND: The immunoglobulin superfamily protein Trem2 (triggering receptor expressed on myeloid cells 2) is primarily expressed on myeloid cells where it functions to regulate macrophage-related immune response induction. While macrophages are essential mediators of diabetic wound healing, the specific regulatory role that Trem2 plays in this setting remains to be established. OBJECTIVE: This study was developed to explore the potential importance of Trem2 signalling in diabetic wound healing and to clarify the underlying mechanisms through which it functions. METHODS AND RESULTS: Following wound induction, diabetic model mice exhibited pronounced upregulation of Trem2 expression, which was primarily evident in macrophages. No cutaneous defects were evident in mice bearing a macrophage-specific knockout of Trem2 (T2-cKO), but they induced more pronounced inflammatory responses and failed to effectively repair cutaneous wounds, with lower levels of neovascularization, slower rates of wound closure, decreased collagen deposition following wounding. Mechanistically, we showed that interleukin (IL)-4 binds directly to Trem2, inactivating MAPK/AP-1 signalling to suppress the expression of inflammatory and chemoattractant factors. Co-culture of fibroblasts and macrophages showed that macrophages from T2-cKO mice suppressed the in vitro activation and proliferation of dermal fibroblasts through upregulation of leukaemia inhibitory factor (Lif). Injecting soluble Trem2 in vivo was also sufficient to significantly curtail inflammatory responses and to promote diabetic wound healing. CONCLUSIONS: These analyses offer novel insight into the role of IL-4/Trem2 signalling as a mediator of myeloid cell-fibroblast crosstalk that may represent a viable therapeutic target for efforts to enhance diabetic wound healing.

Assuntos

Interleucina-4 , Glicoproteínas de Membrana , Receptores Imunológicos , Cicatrização , Animais , Receptores Imunológicos/metabolismo , Receptores Imunológicos/genética , Cicatrização/genética , Glicoproteínas de Membrana/metabolismo , Glicoproteínas de Membrana/genética , Camundongos , Interleucina-4/metabolismo , Interleucina-4/genética , Camundongos Knockout , Modelos Animais de Doenças , Diabetes Mellitus Experimental/metabolismo , Macrófagos/metabolismo , Masculino , Camundongos Endogâmicos C57BL

RESUMO

Light is a vital environmental signal that regulates the expression of plastid genes. Plastids are crucial organelles that respond to light, but the effects of light on plastid RNA processing following transcription remain unclear. In this study, we systematically examined the influence of light exposure on plastid RNA processing, focusing on RNA splicing and RNA editing. We demonstrated that light promotes the splicing of transcripts from the plastid genes rps12, ndhA, atpF, petB, and rpl2. Additionally, light increased the editing rate of the accD transcript at nucleotide 794 (accD-794) and the ndhF transcript at nucleotide 290 (ndhF-290), while decreasing the editing rate of the clpP transcript at nucleotide 559 (clpP-559). We have identified key regulators of signaling pathways, such as CONSTITUTIVELY PHOTOMORPHOGENIC 1 (COP1), ELONGATED HYPOCOTYL 5 (HY5), and PHYTOCHROME-INTERACTING FACTORs (PIFs), as important players in the regulation of plastid RNA splicing and editing. Notably, COP1 was required for GENOMES UNCOUPLED1 (GUN1)-dependent repression of clpP-559 editing in the light. We showed that HY5 and PIF1 bind to the promoters of nuclear genes encoding plastid-localized RNA processing factors in a light-dependent manner. This study provides insight into the mechanisms underlying light-mediated post-transcriptional regulation of plastid gene expression.

RESUMO

Nutritional risk screening 2002 (NRS2002) is a commonly used tool for screening the risk of malnutrition in hospitalized patients, while patient-generated subjective global assessment (PG-SGA) is a nutritional assessment tool for malignant tumor patients. However, there are still gaps in the rapid nutritional risk screening methods for cancer patients. We aimed to evaluate the value of abridged scored patient-generated subjective global assessment (abPG-SGA) for nutritional risk screening and prognosis in cancer patients. The NRS 2002 and abPG-SGA scores of 100 malignant tumor patients hospitalized in our department in December 2020 were collected. Take NRS2002 ≥ 3 as the positive standard (risk of malnutrition). Data were analyzed using Kappa test, ROC curves, cut-off values and Kaplan-Meier. In the screening of 100 patients, 25.0% of patients were at risk of malnutrition (NRS2002), abPG-SGA yielded a sensitivity and specificity of 92.0% and 72.0%, respectively (area under curve [AUC] = 0.884, cut-off value ≥ 4.5); In the screening of patients with digestive system malignancies, 22.6% of patients were at risk of malnutrition (NRS2002), and the sensitivity and specificity of abPG-SGA were 91.67% and 87.80%, respectively (AUC = 0.945, cut-off value ≥ 5.5). The results of survival analysis showed that the overall survival (OS) of patients with abPG-SGA ≥ 5 and < 5, NRS2002 ≥ 3 and abPG-SGA < 5, NRS2002 < 3 and abPG-SGA ≥ 5 were significantly different (P < .0001), the OS of patients with NRS2002 ≥ 3 and abPG-SGA ≥ 5, NRS2002 < 3 and abPG-SGA < 5 were not significantly different (P > .05). Like NRS2002, abPG-SGA can also be used for malnutrition screening and prognosis judgment in cancer patients. It can quickly screen out cancer patients who may be at risk of malnutrition and facilitate the development of nutritional assessments.

Assuntos

Desnutrição , Neoplasias , Avaliação Nutricional , Humanos , Feminino , Masculino , Neoplasias/complicações , Desnutrição/diagnóstico , Pessoa de Meia-Idade , Idoso , Medição de Risco/métodos , Adulto , Estado Nutricional , Sensibilidade e Especificidade , Prognóstico , Curva ROC , Programas de Rastreamento/métodos

RESUMO

PURPOSE: To assess the reproducibility of radiomic features (RFs) extracted from dynamic contrast-enhanced computed tomography (DCE-CT) scans of patients diagnosed with hepatocellular carcinoma (HCC) with regards to inter-observer variability and acquisition timing after contrast injection. The predictive ability of reproducible RFs for differentiating between the degrees of HCC differentiation is also investigated. METHODS: We analyzed a set of DCE-CT scans of 39 patients diagnosed with HCC. Two radiologists independently segmented the scans, and RFs were extracted from each sequence of the DCE-CT scans. The same lesion was segmented across the DCE-CT sequences of each patient's scan. From each lesion, 127 commonly used RFs were extracted. The reproducibility of RFs was assessed with regard to (i) inter-observer variability, by evaluating the reproducibility of RFs between the two radiologists; and (ii) timing of acquisition following contrast injection (inter- and intra-imaging phase). The reproducibility of RFs was assessed using the concordance correlation coefficient (CCC), with a cut-off value of 0.90. Reproducible RFs were used for building XGBoost classification models for the differentiation of HCC differentiation. RESULTS: Inter-observer analyses across the different contrast-enhancement phases showed that the number of reproducible RFs was 29 (22.8%), 52 (40.9%), and 36 (28.3%) for the non-contrast enhanced, late arterial, and portal venous phases, respectively. Intra- and inter-sequence analyses revealed that the number of reproducible RFs ranged between 1 (0.8%) and 47 (37%), inversely related with time interval between the sequences. XGBoost algorithms built using reproducible RFs in each phase were found to be high predictive ability of the degree of HCC tumor differentiation. CONCLUSIONS: The reproducibility of many RFs was significantly impacted by inter-observer variability, and a larger number of RFs were impacted by the difference in the time of acquisition after contrast injection. Our findings highlight the need for quality assessment to ensure that scans are analyzed in the same physiologic imaging phase in quantitative imaging studies, or that phase-wide reproducible RFs are selected. Overall, the study emphasizes the importance of reproducibility and quality control when using RFs as biomarkers for clinical applications.

Assuntos

Carcinoma Hepatocelular , Meios de Contraste , Neoplasias Hepáticas , Variações Dependentes do Observador , Tomografia Computadorizada por Raios X , Humanos , Carcinoma Hepatocelular/diagnóstico por imagem , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/patologia , Masculino , Feminino , Tomografia Computadorizada por Raios X/métodos , Reprodutibilidade dos Testes , Pessoa de Meia-Idade , Idoso , Adulto , Radiômica

RESUMO

Since time immortal, people have used the well-known Chinese Chaenomeles fruit Xuan-Mugua for both traditional medicine and nourishment. With an aim to explore the digestive and antioxidant properties of the phenolics, Xuan-Mugua peel and pulp were extracted, digested and analyzed in vitro. Our results indicated that the total phenolics content (TPC), total flavonoids content (TFC) and the antioxidant activity of the peel were 3.24-8.89 times higher than that of pulp. The contents and activity of the peel and pulp consistently dropped in the sequence of oral, gastric, and small intestine digestions, from 22.78 % to 52.16 %. With a level of 1.590 ± 0.060 and 0.395 ± 0.015 mg g-1 dried weight in the peel and pulp, respectively, chlorogenic acid was the primary phenolic ingredient in Xuan-Mugua, with a promising recovery (81.39-82.23 %) during the digestion. According to these results, Xuan-Mugua exhibited an appreciable level of phenolic content and antioxidant activity during digestion, making it a suitable ingredient for use in functional foods.

RESUMO

Objective: To understand and analyze the factors relating to patient and diagnostic delays among groups with tuberculous pleurisy (TP), and its spatiotemporal distribution in Zhejiang Province. Methods: Data of all tuberculous pleurisy patients were collected from the existing Tuberculosis Information Management System. A time interval of > 2 weeks between first symptom onset and visit to the designated hospital was considered a patient delay, and a time interval of > 2 weeks between the first visit and a confirmed TP diagnosis was considered a diagnostic delay. Univariate and multivariate logistic regression analyses were used to explore factors influencing patient and diagnostic delays in patients with TP. Spatial autocorrelation and spatiotemporal scan analyses were used to identify hot spots and risk clusters, respectively. Results: In total, 10,044 patients with TP were included. The median time and interquartile range for patients seeking medical care and diagnosis were 15 (7-30) and 1 (0-8) days, respectively. The results showed that people aged > 65 years, retirees, and residents of Jinhua, Lishui, and Quzhou were positively correlated with patient delay, whereas retreatment patients, houseworkers, unemployed people, and residents of Zhoushan or Ningbo were positively correlated with diagnostic delay. Additionally, high-risk clusters of patient delays were observed in the midwestern Zhejiang Province. The most likely clusters of TP diagnostic delays were found in southeast Zhejiang Province. Conclusion: In summary, patient delay of TP in Zhejiang province was shorter than for pulmonary tuberculosis in China, while the diagnostic delay had no difference. Age, city, occupation, and treatment history were related to both patient and diagnostic delays in TP. Interventions in central and western regions of Zhejiang Province should be initiated to improve the early detection of TP. Additionally, the allocation of health resources and accessibility of health services should be improved in the central and eastern regions of Zhejiang Province.

Assuntos

Diagnóstico Tardio , Análise Espaço-Temporal , Tuberculose Pleural , Humanos , China/epidemiologia , Tuberculose Pleural/diagnóstico , Tuberculose Pleural/epidemiologia , Feminino , Diagnóstico Tardio/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Idoso , Adulto , Adolescente , Adulto Jovem

RESUMO

This study investigated the role and mechanism of ligustilide(LIG) in attenuating oxygen-glucose deprivation/reoxyge-nation(OGD/R)-induced damage to mouse hippocampal neuron cells(HT22) by inhibiting ferroptosis through mitochondrial ferritin(FtMt). An in vitro model of OGD/R-induced HT22 cell damage was established. HT22 cells were randomly divided into normal group, model group, LIG groups(5, 10, and 20 µmol·L~(-1)), and ferrostatin-1(Fer-1, 2 µmol·L~(-1)) group. Cell viability was mea-sured using the CCK-8 method, and lactate dehydrogenase(LDH) release was measured using an LDH assay kit. Cell morphology was observed under an inverted microscope, and mitochondrial ultrastructure was observed using transmission electron microscopy. Intracellular Fe~(2+) content was detected using a chemiluminescence method. To further investigate the mechanism of FtMt inhibition of ferroptosis, FtMt in HT22 cells was silenced and divided into normal group, model group, LIG group(20 µmol·L~(-1)), si-NC group, si-FtMt group, and si-FtMt+20 µmol·L~(-1) LIG group. Immunofluorescence and Western blot were used to detect FtMt expression. Chemiluminescence was used to measure the content of NADPH/NADP~+, GSH, MDA, and ATP in HT22 cells. The mtROS fluorescence intensity was observed by laser confocal microscopy, and intracellular Fe~(2+) content was measured by flow cytometry. The expression of ferroptosis-related proteins Ferrtin, GPX4, and ACSL4 was detected by Western blot. The results showed that compared with the model group, LIG significantly increased the survival rate of HT22 cells, improved the morphology of damaged HT22 cells and mitochondrial ultrastructure, decreased intracellular Fe~(2+) content, and reduced the expression of the pro-ferroptosis protein ACSL4 while increasing the expression of anti-ferroptosis proteins Ferrtin and GPX4. After silencing FtMt, LIG promoted FtMt expression. Compared with the si-FtMt group, LIG significantly increased the content of NADPH/NADP~+ and GSH, reduced mtROS fluorescence intensity and MDA content, increased ATP activity, decreased intracellular Fe~(2+) content, inhibited the expression of pro-ferroptosis protein ACSL4, and increased the expression of anti-ferroptosis proteins Ferrtin and GPX4. In summary, LIG improved mitochondrial function by upregula-ting FtMt expression to inhibit ferroptosis, thereby alleviating OGD/R-induced damage to HT22 cells.

Assuntos

4-Butirolactona , Ferroptose , Glucose , Animais , Ferroptose/efeitos dos fármacos , Camundongos , 4-Butirolactona/análogos & derivados , 4-Butirolactona/farmacologia , Glucose/metabolismo , Hipocampo/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/citologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Oxigênio/metabolismo , Linhagem Celular , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo

RESUMO

Reusing reclaimed water requires stringent disinfection but inevitably generates disinfection by-products (DBPs). H2O2/O3 treatment is an efficient and environmentally benign disinfection method. For the first time, our bioassay results elucidate that low H2O2/O3 ratio (molar) treated water increased unignorable toxicity effect compared to that of the high H2O2/O3 ratio. To clarify this finding, individual organic brominated DBPs (Br-DBPs), bromate, and adsorbable organic bromine (AOBr) were considered due to their potential risk. Organic Br-DBPs were mainly generated from ozone-induced pathways. Individual organic Br-DBPs were not the primary concern in this scenario because they are typically only produced in observable quantities at bromide concentrations exceeding 500 µg/L, and even then, they often remain below detection limits when treated with H2O2/O3. On the contrary, both bromate and AOBr were detectable at low H2O2/O3 ratios. Furthermore, bromate is produced from HOBr and bromine radicals induced by HO•. Moreover, bromate formation was promoted because of increased HO• formation, particularly at H2O2/O3 ratios <0.24. To prevent HO•-induced pathways from being dominant, higher H2O2/O3 ratios (>0.48) were required. Toxicity assays revealed that AOBr-included organic extracts of ozonated reclaimed water induced more toxic effects. The toxicity induced by the organic fraction resulted from its decreased oxidation level, which was, in turn, driven by the increased formation of bromate. Enhanced toxicity effects were observed when cells were exposed to a bromate and organic extract mixture. It indicates that both the AOBr and bromate present in low-H2O2-O3-treated reclaimed water pose potential risks, and their coexistence further elevates these risks. Increasing the H2O2/O3 ratio markedly decreased the generation of intracellular oxidative substances and oxidative damage. In conclusion, when treated with H2O2/O3, shifting from HO•-induced pathways to ozone-induced pathways by a relatively high H2O2/O3 ratio decreased the amounts of DBPs produced and controlled the toxic effects to ensure the safety of ozonated reclaimed water.

RESUMO

Mercury ions (Hg2+) are highly toxic heavy metals that are commonly found in natural environments. Owning to their non-biodegradability and accumulation in the food chain, the precise detection of trace amounts of Hg2+ is essential for preventing chronic accumulation and ensuring food safety. In this study, we present a dual-mode paper sensor for simultaneous colorimetric and Surface-Enhanced Raman Spectroscopy (SERS) detection of Hg2+ in tea, achieving ultrasensitive, rapid, and on-site screening. 4-Mercaptopyridine (4-MPY) was effectively chemisorbed onto the gold nanoparticles (AuNPs), acting as a signal probe for colorimetric methods. Moreover, it can produce plasmonic hot spots for SERS by interacting with the pyridine ring. To enhance the signal intensity of both colorimetry and SERS, a silver shell is in-situ grown on the surface of AuNPs captured on the paper sensor by reduction of Ag+, achieving signal amplification. The visual limit of detection (LOD) for the colorimetric biosensor is 2.5 pM, while the LOD of SERS is 0.48 pM with this dual-mode paper sensor. The sensitivity of both the colorimetric method and SERS was improved by approximately 200 and 500 times, respectively, with the designed signal amplification strategy. The system allows for multiple parallel screening of the same sample, ensuring accurate results without any false-positive or false-negative. This study provides a valuable platform for the accurate detection of various other heavy metal ions and provides effective strategies for improving the performance of colorimetric methods.

RESUMO

Two sulfur-containing heterodimers of a cytochalasan and a macrolide, sucurchalasins A and B (1 and 2), and four known cytochalasan monomers (3-6), as well as four known macrolide derivatives (7-10), were obtained from the endophytic fungus Aspergillus spelaeus GDGJ-286. Sucurchalasins A and B (1 and 2) are the first cytochalasan heterodimers formed via a thioether bridge between cytochalasan and curvularin macrolide units. Their structures were elucidated by detailed analysis of NMR, LC-MS/MS, and X-ray crystallography. In bioassays, 1 and 2 exhibited cytotoxic effects on A2780 cells, with IC50 values of 3.9 and 8.3 µM, respectively. They also showed antibacterial activities against E. faecalis and B. subtilis with MIC values of 3.1 and 6.3 µg/mL, respectively.

Assuntos

Aspergillus , Citocalasinas , Macrolídeos , Aspergillus/química , Citocalasinas/farmacologia , Citocalasinas/química , Citocalasinas/isolamento & purificação , Macrolídeos/farmacologia , Macrolídeos/química , Estrutura Molecular , Humanos , Testes de Sensibilidade Microbiana , Antibacterianos/farmacologia , Antibacterianos/química , Enxofre/química , Cristalografia por Raios X , Bacillus subtilis/efeitos dos fármacos

RESUMO

Intracellular cargo delivery is crucial for drug evaluation, nanomedicine development, and gene therapy, in which high efficiency while maintaining cell viability is needed for downstream analysis. Here, an acoustic-mediated precise drug delivering mechanism is proposed by directly modulating cell micro-oscillation mode and membrane permeability. Through phase shifting keying-based spatiotemporal acoustic tweezers, controllable oscillating cell arrays can be achieved in shaking potentials. At the same time, continually oscillating radiation force and fluid shear stress exerted on cells effectively disturbs cellular membrane mobility and enhances permeability, thereby facilitating nanodrug entrance. In experiments, cell oscillation is tunable in frequency (10-2 to 102 Hz), shaking direction, amplitude (0 to quarter acoustic wavelength), and speed. Doxorubicin is actively delivered across cellular membranes and accumulates in inner cells, with a concentration more than 8 times that of the control group. Moreover, there is no obvious compromise in cell activity during oscillation, exhibiting excellent biocompatibility. This "dancing acoustic waves" scheme introduces a new dimension of cell manipulation in both space and time domains and an effective drug delivering strategy, offering advantages of flexibility, gentleness, and high throughput. It may advance related fields like nanobiological research, drug and nanomedicine development, and medical treatment.

Assuntos

Acústica , Doxorrubicina , Sistemas de Liberação de Medicamentos , Doxorrubicina/farmacologia , Doxorrubicina/química , Humanos , Sobrevivência Celular/efeitos dos fármacos , Antibióticos Antineoplásicos/farmacologia , Antibióticos Antineoplásicos/química

RESUMO

In the field of spinal pathology, sagittal balance of the spine is usually judged by the spatial structure and morphology of pelvis, which can be represented by pelvic parameters. Pelvic parameters, including pelvic incidence, pelvic tilt and sacral slope, are therefore essential for the diagnosis and treatment of spinal disorders, however, it is a time-consuming and laborious procedure to measure these parameters by traditional methods. In this paper, an automatic measurement framework for pelvic CT images was proposed to calculate three-dimensional (3D) pelvic parameters with the support of deep learning technology. Pelvic images were first preprocessed, and 3D reconstruction was then performed to obtain 3D pelvic model by the Visualization Toolkit. DRINet was trained to segment the femoral head region in the pelvic images, and 3D sphere fitting was performed to locate the femoral heads. In addition, VGG16 was adopted to recognize images containing superior sacral endplate, and the plane growth algorithm was used to fit the plane so that the midpoint and normal vector of the superior sacral endplate could be obtained. Finally, 3D pelvic parameters were automatically calculated, and compared with manual measurements for 15 patients. The proposed framework automatically generated 3D pelvic models, and calculated two-dimensional (2D) and 3D pelvic parameters from continuous CT images. Experiments demonstrated that the framework can greatly speed up the calculation of pelvic parameters, and these parameters are accurate when compared with the manual measurements. In conclusion, the proposed framework demonstrates good performance on automatic pelvimetry measurement by incorporating deep learning technology, and can well replace the traditional methods for pelvic parameter measurement.

Assuntos

Aprendizado Profundo , Imageamento Tridimensional , Pelve , Tomografia Computadorizada por Raios X , Humanos , Tomografia Computadorizada por Raios X/métodos , Imageamento Tridimensional/métodos , Pelve/diagnóstico por imagem , Pelvimetria/métodos , Algoritmos , Feminino , Masculino , Adulto , Pessoa de Meia-Idade , Cabeça do Fêmur/diagnóstico por imagem

RESUMO

Antimicrobial resistance poses an escalating threat to human health, necessitating the development of novel antimicrobial agents capable of addressing challenges posed by antibiotic-resistant bacteria. Thanatin, a 21-amino acid ß-hairpin insect antimicrobial peptide featuring a single disulfide bond, exhibits broad-spectrum antibacterial activity, particularly effective against multidrug-resistant strains. The outer membrane biosynthesis system is recognized as a critical vulnerability in antibiotic-resistant bacteria, which thanatin targets to exert its antimicrobial effects. This peptide holds significant promise for diverse applications. This review begins with an examination of the structure-activity relationship and synthesis methods of thanatin. Subsequently, it explores thanatin's antimicrobial activity, detailing its various mechanisms of action. Finally, it discusses prospective clinical, environmental, food, and agricultural applications of thanatin, offering valuable insights for future research endeavors.

Assuntos

Peptídeos Catiônicos Antimicrobianos , Farmacorresistência Bacteriana Múltipla , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Humanos , Peptídeos Catiônicos Antimicrobianos/farmacologia , Peptídeos Catiônicos Antimicrobianos/química , Antibacterianos/farmacologia , Antibacterianos/química , Relação Estrutura-Atividade , Animais , Bactérias/efeitos dos fármacos , Peptídeos Antimicrobianos/farmacologia , Peptídeos Antimicrobianos/química , Testes de Sensibilidade Microbiana

RESUMO

The hydration heat generated during the concreting of cast-in-place piles causes thermal disturbance to the surrounding permafrost, leading to its thawing. This further affects the stability of the pile foundation and degrades the construction progress. To explore the influence mechanisms of the concrete hydration heat on the permafrost temperature field around the pile, as well as that of different construction seasons on the pile-side boundary conditions and permafrost temperature field, monitoring results of on-site tests and numerical simulation were used to analyze the distribution law of the pile soil temperature field in space and time, and the pile-side boundary conditions and permafrost temperature field during construction seasons. The results show that the temperature trend of the pile foundation can be divided into three stages: a rapid rise phase (0∼2 d), a rapid decline phase (2∼10 d), and a slow decline and stabilization phase (10∼90 d). As the radial distance from the pile center decreases, there occur a corresponding acceleration in temperature increase and an elevated maximum temperature rise (MTR). The influence range of the molding temperature and the hydration heat is about 1∼2 times the pile diameter and less than 1.5 m in the depth direction. Compared to the atmospheric temperature, there is a lag in the change in the permafrost temperature caused by accumulation of ground temperature, and the significant difference between the two leads to an increased rate of heat exchange at the boundary condition. Conducting drilling operation and cast-in-place pile construction in the cold seasons is conducive to reducing the thermal disturbance to the permafrost around the pile in permafrost areas.

RESUMO

BACKGROUND: Several studies have suggested an association between vitamin deficiency and the development of tuberculosis; however, the precise impact remains unclear. This study aimed to elucidate the relationship between distinct vitamin statuses and the occurrence of tuberculosis. MATERIALS AND METHODS: Retrieval was conducted using several databases without language restrictions to capture the eligible studies on tuberculosis and vitamin status. Pooled odds ratios (ORs), relative risks (RRs), and hazard ratios (HRs) were used with 95% confidence intervals (CIs) to clarify the relationship between the different vitamin statuses (A, B, D, and E) and the occurrence of tuberculosis. Subgroup analysis, sensitivity analysis, meta-regression analysis, and Galbraith plot were performed to determine sources of heterogeneity. Potential publication biases were detected using Begg's test, Egger's test, and the trim-and-fill test. RESULTS: We identified 10,266 original records from our database searches, and 69 eligible studies were considered in this study. The random-effect model showed that people with tuberculosis may exhibit vitamin A deficiency (OR = 10.66, 95%CI: 2.61-43.63, p = .001), while limited cohort studies showed that vitamin A supplementation may reduce tuberculosis occurrence. Additionally, vitamin D deficiency was identified as a risk factor for tuberculosis development (RR = 1.69, 95%CI: 1.06-2.67, p = .026), and people with tuberculosis generally had lower vitamin D levels (OR = 2.19, 95%CI: 1.76-2.73, p < .001) compared to other groups. No publication bias was detected. CONCLUSIONS: This meta-analysis indicated that people with tuberculosis exhibited low levels of vitamins A and D, while vitamin D deficiency was identified as a risk factor for tuberculosis. More randomized controlled interventions at the community levels should be recommended to determine the association between specific vitamin supplementation and tuberculosis onset.

Assuntos

Tuberculose , Deficiência de Vitamina A , Deficiência de Vitamina D , Humanos , Tuberculose/epidemiologia , Deficiência de Vitamina D/epidemiologia , Deficiência de Vitamina D/complicações , Deficiência de Vitamina A/epidemiologia , Deficiência de Vitamina A/complicações , Deficiência de Vitamina A/sangue , Fatores de Risco , Vitamina A/sangue , Suplementos Nutricionais , Vitaminas/sangue , Vitamina D/sangue , Deficiência de Vitamina E/epidemiologia , Deficiência de Vitamina E/complicações , Deficiência de Vitamina E/sangue , Feminino , Masculino , Razão de Chances , Adulto , Vitamina E/sangue

RESUMO

Blinatumomab has emerged as a promising component of first-line therapy for acute B-cell precursor lymphoblastic leukemia (BCP-ALL), bolstering treatment efficacy. To mitigate CD19 selection pressure and reduce the incidence of blinatumomab-associated toxicities, pre-treatment chemotherapy is recommended before administering blinatumomab. From September 2022 to December 2023, we conducted a single-arm, multicenter, phase 2 trial (NCT05557110) in newly diagnosed Philadelphia chromosome-negative BCP-ALL (Ph-negative BCP-ALL) patients. Participants received induction treatment with reduced-dose chemotherapy (RDC), comprising idarubicin, vindesine, and dexamethasone over 7 days, followed by 2 weeks of blinatumomab. Those failing to achieve composite complete remission (CRc) received an additional 2 weeks of blinatumomab. The primary endpoint was the CRc rate post initial induction treatment. Of the 35 enrolled patients, 33 (94%) achieved CRc after 2 weeks of blinatumomab, with 30 (86%) achieving measurable residual disease (MRD) negativity. Two patients extended blinatumomab to 4 weeks. With either 2 or 4 weeks of blinatumomab treatment, all patients achieved CR (35/35) and 89% (31/35) were MRD negativity. The median time to CR was 22 days. Immune effector cell-associated neurotoxicity syndrome was limited (14%, all grade 1). Non-hematological adverse events of grade 3 or higher included pneumonia (17%), sepsis (6%), and cytokine release syndrome (9%). With a median follow-up of 11.5 months, estimated 1-year overall survival and 1-year progression-free survival rates were 97.1% and 82.2%, respectively. These findings affirm that RDC followed by blinatumomab is an effective and well-tolerated induction regimen for newly diagnosed Ph-negative BCP-ALL, supporting a shift towards less intensive and more targeted therapeutic approaches. Trial registration: https://www.clinicaltrials.Gov . Identifier NCT05557110.

Assuntos

Anticorpos Biespecíficos , Protocolos de Quimioterapia Combinada Antineoplásica , Quimioterapia de Indução , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Humanos , Anticorpos Biespecíficos/uso terapêutico , Anticorpos Biespecíficos/administração & dosagem , Anticorpos Biespecíficos/efeitos adversos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Adulto Jovem , Quimioterapia de Indução/métodos , Idoso , Adolescente , Dexametasona/administração & dosagem , Dexametasona/uso terapêutico , Dexametasona/efeitos adversos , Indução de Remissão

RESUMO

Probiotics can improve animal growth performance and intestinal health. However, understanding the effects of paraprobiotics on the growth performance and gut microbiota of piglets and how the paraprobiotics exert their impact are still limited. The present study was conducted to investigate the effects of heat-killed Lactobacillus acidophilus IFFI 6005 supplementation on the growth performance, intestinal microbiota, and fecal metabolites of piglets. First, a feed-additive sample of heat-killed Lactobacillus acidophilus IFFI 6005 was prepared by culture. Second, 96 (initial BW = 14.38 ± 0.67 kg, weaning age of 40 days) healthy piglets were selected and randomized into four treatment groups. Each treatment group consisted of three replicates (n = 8). Pigs were fed a basal diet (NC), basal diet plus antibiotics (PC), basal diet plus Lactobacillus acidophilus IFFI 6005 at 600 g/t (LA, 1.0 × 1010 cfu/g), and basal diet plus heat-killed Lactobacillus acidophilus IFFI 6005 at 600 g/t (HKLA), respectively; the trial lasted for 30 days. The results showed that the ratios of feed to gain (F:G) and diarrhea rate of both the HKLA and PC groups were significantly lower compared with the NC and LA groups (p < 0.05); however, there was no significant difference between the HKLA and PC group (p > 0.05). In addition, the average daily weight gain (ADG) of the HKLA group was significantly higher (p < 0.05) than that of the other three groups in terms of growth performance. Finally, 16S rRNA sequencing and metabolome analysis based on fecal samples further elaborated that the addition of heat-killed Lactobacillus acidophilus IFFI 6005 to the feed improved the intestinal microbial diversity and abundance (p < 0.05) and reduced the abundance of pathogenic bacteria (p < 0.05), but it did not affect the abundance of Lactobacillus (p > 0.05). Through the comparison of microbial abundance and metabolite content between the two groups (NC_vs_HKLA), the largest differences were found in six microorganisms and 10 metabolites in the intestine (p < 0.05). These differential metabolites were involved in the digestion, absorption and utilization of protein and starch, as well as in oxidative stress. In summary, addition of heat-killed Lactobacillus acidophilus IFFI 6005 as a new feed additive in piglets has beneficial effects on the growth performance, intestinal bacteria and metabolites, and can be used as an alternative to antibiotics.

RESUMO

PURPOSE: This study aimed to develop, validate, and evaluate machine learning (ML) algorithms for predicting Surgical site infections (SSI) and surgical site occurrences (SSO) after elective open inguinal hernia surgery. METHODS: A cohort of 491 patients who underwent elective open inguinal hernia surgery at Fudan University Affiliated Huadong Hospital between December 2019 and December 2020 was enrolled. To create a strong prediction model, we employed five ML methods: generalized linear model, random forest (RF), support vector machines, neural network, and gradient boosting machine. Based on the best performing model, we devised online calculators to facilitate clinicians' access to a linear predictor for patients. The receiver operating characteristic curve was utilized to evaluate the model's discriminatory capability and predictive accuracy. RESULTS: The incidence rates of SSI and SSO were 4.68% and 13.44%, respectively. Four variables (diabetes, recurrence, antibiotic prophylaxis, and duration of surgery) were identified for SSI prediction, while four variables (diabetes, size of hernias, albumin levels, and antibiotic prophylaxis) were included for SSO prediction. In the test set, the RF model showed the best predictive ability (SSI: area under the curve (AUC) = 0.849, sensitivity = 0.769, specificity = 0.769, and accuracy = 0.769; SSO: AUC = 0.740, sensitivity = 0.513, specificity = 0.821, and accuracy = 0.667). Online calculators have been developed to assess patients' risk of SSI ( https://wuqian17.shinyapps.io/predictionSSI/ ) and SSO ( https://wuqian17.shinyapps.io/predictionSSO/ ) after surgery. CONCLUSIONS: This study developed a prediction model for SSI/SSO using ML methods. It holds the potential to facilitate the selection of appropriate treatment options following elective open inguinal hernia surgery.

RESUMO

Background: The actual situation and influencing factors of prophylactic use of proton pump inhibitors (PPIs) in internal medicine inpatients receiving glucocorticoid therapy are rarely reported. This study aimed to investigate the current status and influencing factors of prophylactic use of PPIs in internal medicine inpatients receiving glucocorticoid therapy to provide a basis for rational prophylactic use of PPIs. Methods: Internal medicine inpatients receiving glucocorticoid therapy from February 2023 to September 2023 were included. Information on the prophylactic use of PPIs was collected and analyzed by clinical pharmacists. Associated factors with prophylactic use of PPIs were analyzed by univariable and multivariable logistic regression. Results: 980 inpatients were finally included in our study, of which 271 (27.7%) inpatients received prophylactic use of PPIs. Among the inpatients prescribed PPIs, 90 inpatients received a standard dose of PPIs twice a day. Multiple logistic regression analysis showed that age ≥80 years [OR = 7.009, 95% CI (1.424, 34.495), p = 0.017], history of gastroesophageal reflux disease (GERD) [OR = 2.047, 95% CI (1.338, 3.133), p = 0.001], low platelet count [OR = 0.997, 95% CI (0.994, 0.999), p = 0.004], number of concomitant diseases [OR = 1.104, 95% CI (1.056, 1.153), p < 0.001], junior doctors [OR = 1.755, 95% CI (1.248, 2.468), p = 0.001], glucocorticoid dose (higher than 50 mg, measured by methylprednisolone) [OR = 2.455, 95% CI (1.371, 4.395), p = 0.003], antiplatelet agents [OR = 2.567, 95% CI (1.456, 4.524), p = 0.001], immunosuppressants [OR = 1.477, 95% CI (1.014, 2.153), p = 0.042], and betahistine [OR = 5.503, 95% CI (1.124, 26.950), p = 0.035] were associated with more prophylactic use of PPIs. Conclusion: The prophylactic use of PPIs in internal medicine inpatients receiving glucocorticoid therapy is common in China. Clinical pharmacists will take targeted measures to promote the rational use of PPIs according to the results of this study.