Search

Abstract Background A significant number of adverse drug reactions is caused by unexpected Drug-drug interactions (DDIs). The identification of DDIs becomes crucial before the co-prescription of multiple drugs is made. Such a task in clinics or in drug discovery usually requires high costs and numerous limitations, while computational approaches are able to predict potential DDIs effectively by utilizing diverse drug attributes (e.g. side effects). Nevertheless, they’re incapable when required to predict enhancive and degressive DDIs, which change increasingly and decreasingly the pharmacological behavior of interacting drugs respectively. The pharmacological change of DDIs is one of the most important factors when making a multi-drug prescription. Results In this work, we design a Triple Matrix Factorization-based Unified Framework (TMFUF) to address the above issue. By leveraging a group of side effect entries of drugs, TMFUF achieves the inspiring result (AUC = 0.842 and AUPR = 0.526) in the case of conventional DDI prediction under the traditional screening task. In the comparison with two state-of-the-art approaches, TMFUF demonstrates it superiority by ~ 7% and ~ 20% improvement in terms of AUC and AUPR respectively. More importantly, TMFUF shows its ability in the comprehensive DDI prediction under different screening tasks. Finally, a utilization TMFUF reveals the significant pairs of side effects, which contribute to form enhancive and degressive DDIs, for further clinical validation. Conclusions The proposed TMFUF is first capable to predict both conventional binary DDIs and comprehensive DDIs such that it captures the pharmacological changes caused by DDIs. Furthermore, it provides a unified solution of DDI prediction for two screening scenarios, which involves newly given drugs having no prior interaction. Another advantage is its ability to indicate how significantly the pairs of drug features contribute to form DDIs.

Abstract Background The investigation of the genetic basis of local adaptation in non-model species is an interesting focus of evolutionary biologists and molecular ecologists. Identifying these adaptive genetic variabilities on the genome responsible can provide insight into the genetic mechanism of local adaptation. Results We investigated the spatial distribution of genetic variation in 22 natural populations of Pterocarya stenoptera across its distribution area in China to provide insights into the complex interplay between multiple environmental variables and adaptive genetic differentiation. The Bayesian analysis of population structure showed that the 22 populations of P. stenoptera were subdivided into two groups. Redundancy analysis demonstrated that this genetic differentiation was caused by the divergent selection of environmental difference. A total of 44 outlier loci were mutually identified by Arlequin and BayeScan, 43 of which were environment-associated loci (EAL). The results of latent factor mixed model analysis showed that solar radiation in June (Sr6), minimum temperature of the coldest month (Bio6), temperature seasonality (Bio4), and water vapor pressure in January (Wvp1) were associated with the highest numbers of EAL. Sr6 was associated with the ecological habitat of “prefered light”, and Bio6 and Wvp1 were associated with the ecological habitat of “warm and humid environment”. Conclusions Our results provided empirical evidence that environmental variables related to the ecological habitats of species play key roles in driving adaptive differentiation of species genome.

Conventional methods in treating non–small cell lung cancer contain surgery, chemotherapy, radiotherapy, and targeted therapy, which have various defects. Recently, with the deeper research on tumor immunity, immunotherapy has made the breakthrough in the treatment of cancers. Especially developments of programmed cell death-1/programmed cell death ligand-1 (PD-1/PD-L1) inhibitors bring the therapy into a new stage. This review mainly focuses on introducing existing monoclonal antibodies containing nivolumab, pembrolizumab, atezolizumab, avelumab, and durvalumab, along with 3 ordinary biomarkers such as PD-L1 expression, tumor mutation burden, and microsatellite instability. By understanding the resistance mechanism of anti-PD-1/L1 blockade, research is further improving the survival benefit and expanding the benefit population. So, PD-1/PD-L1 inhibitors begin to be combined with various therapeutic strategies clinically. Discussion and comparison of their effectiveness and safety are also comprehensively reviewed. Meanwhile, we explore the potential, the impact, and mechanisms of combining traditional Chinese medicine with immunotherapy.

Abstract Background Drug Combination is one of the effective approaches for treating complex diseases. However, determining combinative drug pairs in clinical trials is still costly. Thus, computational approaches are used to identify potential drug pairs in advance. Existing computational approaches have the following shortcomings: (i) the lack of an effective integration of heterogeneous features leads to a time-consuming training and even results in an over-fitted classifier; and (ii) the narrow consideration of predicting potential drug combinations only among known drugs having known combinations cannot meet the demand of realistic screenings, which pay more attention to potential combinative pairs among newly-coming drugs that have no approved combination with other drugs at all. Results In this paper, to tackle the above two problems, we propose a novel drug-driven approach for predicting potential combinative pairs on a large scale. We define four new features based on heterogeneous data and design an efficient fusion scheme to integrate these feature. Moreover importantly, we elaborate appropriate cross-validations towards realistic screening scenarios of drug combinations involving both known drugs and new drugs. In addition, we perform an extra investigation to show how each kind of heterogeneous features is related to combinative drug pairs. The investigation inspires the design of our approach. Experiments on real data demonstrate the effectiveness of our fusion scheme for integrating heterogeneous features and its predicting power in three scenarios of realistic screening. In terms of both AUC and AUPR, the prediction among known drugs achieves 0.954 and 0.821, that between known drugs and new drugs achieves 0.909 and 0.635, and that among new drugs achieves 0.809 and 0.592 respectively. Conclusions Our approach provides not only an effective tool to integrate heterogeneous features but also the first tool to predict potential combinative pairs among new drugs.

The geological events, past climatic fluctuations, and river systems played key roles in the spatial distribution, population dynamics, and genetic differentiation of species. In this work, we selected Pterocarya stenoptera, a widespread tree species in China, to test the roles of these factors. Four noncoding spacers, eight microsatellite (simple sequence repeat) markers, and species distribution modeling were used to examine the phylogeographical pattern of P. stenoptera. Based on chloroplast DNA data, populations of P. stenoptera were clearly clustered into three groups. The divergence time of these groups fell into the stage of the Qinghai–Tibet Movement, 1.7–2.6 Ma. For simple sequence repeat data, only one western marginal population YNYB could be separated from other populations, whereas other populations were mixed together. Our results indicated that the environmental heterogeneity resulting from the Qinghai–Tibet movement might be response for this genetic divergence. The climatic fluctuations in the Pleistocene did not cause the substantial range shift of P. stenoptera, while the fluctuations affected its population size. Moreover, we also confirmed the river systems did not act as channels or barrier of dispersal for P. stenoptera.

The space scientific payload rack is a multifunctional experimental platform, and the requirements of the environmental temperature index are different for diversified experimental modules inside. The air cooling system is an important part of the rack thermal control system. A new type of air cooling system with small size and flexible arrangement is proposed in this paper, that is, micro air ducts with pinhole-sized air vents. The rack physical models of new and traditional air cooling modes are established, respectively. The numerical simulation of the inner air flow is carried out by Ansys Fluent CFD software (Ansys Inc., Canonsburg, PA, USA), which verifies that compared with the traditional method, the temperature field and flow field of the new air cooling method are more uniform, and the heat sources located at the edge of the rack can also be cooled better.

This paper developed a three-dimensional model to simulate the process of atomization and liquid film formation during the air-blast spray cooling technological process. The model was solved using the discrete phase model method. Several factors including the thermodynamic characteristics of the liquid film as well as the spray quality with different spray mass flow rates under different spray heights were numerically investigated and discussed. The results show that the varied spray height has little effect on the Sauter Mean Diameter (d32) of the spray droplet, while the thermodynamic characteristics of liquid film including the liquid film height, the liquid film velocity, and the liquid film generation rate are sensitive to the change of the spray height. With the growth of spray mass flow rates, d32, the liquid film generation rate and liquid film height become larger, while the liquid film velocity with different spray mass flow rates has a similar velocity distribution, indicating that the spray mass flow rate has little effect on the liquid film velocity. The average d32 of droplet size shows a sharp drop when sprayed from the nozzle in a short period of time ( < 1.5 ms), then approaching smoothness, below a value of 40 , the spray status tends to be stable.

Elite controllers (ECs) are a rare subset of HIV-1 slow progressors characterized by prolonged viremia suppression. HLA alleles B27 and B57 promote the cytotoxic T lymphocyte (CTL)-mediated depletion of infected cells in ECs, leading to the emergence of escape mutations in the viral capsid (CA). Whether those mutations modulate CA detection by innate sensors and effectors is poorly known. Here, we investigated the targeting of CA from B27/B57+ individuals by cytosolic antiviral factors Mx2 and TRIM5α. Toward that aim, we constructed chimeric HIV-1 vectors using CA isolated from B27/B57+ or control subjects. HIV-1 vectors containing B27/B57+-specific CA had increased sensitivity to TRIM5α but not to Mx2. Following exposure to those vectors, cells showed increased resistance against both TRIM5α-sensitive and -insensitive HIV-1 strains. Induction of the antiviral state did not require productive infection by the TRIM5α-sensitive virus, as shown using chemically inactivated virions. Depletion experiments revealed that TAK1 and Ubc13 were essential to the TRIM5α-dependent antiviral state. Accordingly, induction of the antiviral state was accompanied by the activation of NF-κB and AP-1 in THP-1 cells. Secretion of IFN-I was involved in the antiviral state in THP-1 cells, as shown using a receptor blocking antibody. This work identifies innate activation pathways that are likely to play a role in the natural resistance to HIV-1 progression in ECs.

ABSTRACT The PML (promyelocytic leukemia) protein is a member of the TRIM family, a large group of proteins that show high diversity in functions but possess a common tripartite motif giving the family its name. We and others recently reported that both murine PML (mPML) and human PML (hPML) strongly restrict the early stages of infection by HIV-1 and other lentiviruses when expressed in mouse embryonic fibroblasts (MEFs). This restriction activity was found to contribute to the type I interferon (IFN-I)-mediated inhibition of HIV-1 in MEFs. Additionally, PML caused transcriptional repression of the HIV-1 promoter in MEFs. In contrast, the modulation of the early stages of HIV-1 infection of human cells by PML has been investigated by RNA interference, with unclear results. In order to conclusively determine whether PML restricts HIV-1 or not in human cells, we used the clustered regularly interspaced short palindromic repeat with Cas9 (CRISPR-Cas9) system to knock out its gene in epithelial, lymphoid, and monocytic human cell lines. Infection challenges showed that PML knockout had no effect on the permissiveness of these cells to HIV-1 infection. IFN-I treatments inhibited HIV-1 equally whether PML was expressed or not. Overexpression of individual hPML isoforms, or of mPML, in a human T cell line did not restrict HIV-1. The presence of PML was not required for the restriction of nonhuman retroviruses by TRIM5α (another human TRIM protein), and TRIM5α was inhibited by arsenic trioxide through a PML-independent mechanism. We conclude that PML is not a restriction factor for HIV-1 in human cell lines representing diverse lineages. IMPORTANCE PML is involved in innate immune mechanisms against both DNA and RNA viruses. Although the mechanism by which PML inhibits highly divergent viruses is unclear, it was recently found that it can increase the transcription of interferon-stimulated genes (ISGs). However, whether human PML inhibits HIV-1 has been debated. Here we provide unambiguous, knockout-based evidence that PML does not restrict the early postentry stages of HIV-1 infection in a variety of human cell types and does not participate in the inhibition of HIV-1 by IFN-I. Although this study does not exclude the possibility of other mechanisms by which PML may interfere with HIV-1, we nonetheless demonstrate that PML does not generally act as an HIV-1 restriction factor in human cells and that its presence is not required for IFN-I to stimulate the expression of anti-HIV-1 genes. These results contribute to uncovering the landscape of HIV-1 inhibition by ISGs in human cells.

It is of particular interest to use biomass as an alternative source of fuel in direct-reduction ironmaking to ease the current reliance on fossil fuel energy. The influence of cow dung addition on the strength of carbon-bearing iron ore pellets composed of cow dung, iron ore, anthracite, and bentonite was investigated, the quality of green and dry pellet was evaluated based on FTIR analysis, and the mechanism of strength variation of the reduced pellets was investigated by analysing the phase composition and microstructure using XRD and SEM. The results show that cow dung addition decreased the green pellet strength due to expansion of the amorphous region of the cellulose in the cow dung; however, the dry pellet strength increased substantially. In the process of reduction roasting, it was found that cow dung addition can promote aggregation of iron crystals and increase the density of the pellets, resulting in increased strength of the reduction roasted pellets, while excessive cow dung addition resulted in lower strength.

This paper presents an air-oriented spray cooling system (SCS) integrated with a two-phase ejector for the thermal management system. Considering its aeronautical application, the spray nozzle in the SCS is an air-blast one. Heat transfer performance (HTP) of air-water spray cooling was studied experimentally on the basis of the ground-based test. Factors including pressure difference between water-inlet-pressure (WIP) and spray cavity one (PDWIC) and the spray volumetric flow rate (SVFR) were investigated and discussed. Under a constant operating condition, the cooling capacity can be promoted by the growth factors of the PDWIC and SVFR with the values from 51.90 kPa to 235.35 kPa and 3.91 L ⋅ h − 1 to 14.53 L ⋅ h − 1 , respectively. Under the same heating power, HTP is proportional to the two dimensionless parameters Reynolds number and Weber number due to the growth of droplet-impacting velocity and droplet size as the increasing of PDWIC or SVFR. Additionally, compared with the factor of the droplet size, the HTP is more sensitive to the variation in the droplet-impacting velocity. Based on the experimental data, an empirical experimental correlation for the prediction of the dimensionless parameter Nusselt number in the non-boiling region with the relative error of only ± 10 % was obtained based on the least square method.

This paper presents a dynamic health intelligent evaluation model proposed to analyze the health deterioration of satellites under time-varying and extreme thermal loads. New definitions such as health degree and failure factor and new topological system considering the reliability relationship are proposed to characterize the dynamic performance of health deterioration. The dynamic health intelligent evaluation model used the thermal network method (TNM) and fuzzy reasoning to solve the problem of model missing and non-quantization between temperature and failure probability, and it can quickly evaluate and analyze the dynamic health of satellite through the collaborative processing of continuous event and discrete event. In addition, the temperature controller in the thermal control subsystem (TCM) is the target of thermal damage, and the effects of different heat load amplitude, duty ratio, and cycle on its health deterioration are compared and analyzed.

The aerospace-based heat sink is defined as a substance used for dissipating heat generated by onboard heat loads. They are becoming increasingly scarce in the thermal management system (TMS) of advanced aircraft, especially for supersonic aircraft. In the modern aircraft there are many types of heat sinks whose cooling abilities and performance penalties are usually obviously different from each other. Besides, the cooling ability and performance penalty of a single heat sink is even different under different flight conditions—flight altitude, Mach number, etc. In this study, the typical heat sinks which are the fuel mass, ram air, engine fan air, skin heat exchanger, and expendable heat sink will be studied. Their cooling abilities/capacities, and exergy penalties under different flight conditions have been systematically estimated and compared with each other. The exergy penalty presented in this paper refers to the exergy loss of aircraft caused by the extra weight, drag and energy extraction of various heat sinks. The estimation models, as well as the results and discussion have been elaborated in this paper, which can be can be used to further optimize the TMS of modern advanced aircraft, for example, the layout design of various heat sinks and the improvement the control algorithm.

Our aim was to investigate how transcatheter arterial chemoembolization (TACE) combined with percutaneous radiofrequency ablation (RFA) affected liver parenchymal function in patients with hepatocellular carcinoma (HCC), and to evaluate the significant risk factors for post-procedural deterioration of liver function. Methods: Changes in liver laboratory tests and development of complications were monitored in 53 patients with unresectable hepatocellular carcinoma from January 2007 to January 2009. Cox proportional hazard regression model was performed to evaluate risk factors for deterioration of liver function after the procedure. Results: Plasma total bilirubin (TB) increased from pre-procedural 22.1 ± 12.4 μmol/L to 34.1 ± 21.8 μmol/L on post-procedural day three (P = 0.017). Alanine aminotransferase (ALT) also increased greatly from 65 ± 58 IU/L to 285 ± 182 IU/L post-procedurally (P = 0.006). Albumin (ALB) dropped from 42.5 ± 4.5 g/L to 34.6 ± 5.4 g/L (P = 0.019) and the Child–Pugh score increased from 5.2 ± 1.3 to 7.1 ± 1.5 three days after treatment (P = 0.021). Most of these parameters returned to normal range within 3–4 weeks. Thirty-three out of 53 patients developed complications in our study. Cox proportional hazards regression univariate analysis demonstrated that a Child–Pugh score ≥9 points and age ≥60 years were risk factors for deterioration of liver function after the procedure. Furthermore, a Child–Pugh score ≥9 points was found to be the only risk factor for post-procedural deterioration of liver function identified by stepwise multivariate analysis. Conclusion: Liver function parameters such as plasma total bilirubin, ALT, serum ALB and Child–Pugh score could be transiently deteriorated by TACE combined with RFA in patients with Child–Pugh grades B or C. Therefore, patients with a Child–Pugh score ≥9 points were not appropriate candidates for TACE combined with RFA.

During aortic surgery, interruption of spinal cord blood flow might cause spinal cord ischemia-reperfusion injury (IRI). The incidence of spinal cord IRI after aortic surgery is up to 28%, and patients with spinal cord IRI might suffer from postoperative paraplegia or paraparesis. Spinal cord IRI includes two phases. The immediate spinal cord injury is related to acute ischemia. And the delayed spinal cord injury involves both ischemic cellular death and reperfusion injury. Inflammation is a subsequent event of spinal cord ischemia and possibly a major contributor to spinal cord IRI. However, the development of inflammatory mediators is incompletely demonstrated. And treatments available for inflammation in spinal cord IRI are insufficient. Improved understanding about spinal cord IRI and the development of inflammatory cells and cytokines in this process will provide novel therapeutic strategies for spinal cord IRI. Inflammatory cytokines (e.g., TNF-α and IL-1) may play an important role in spinal cord IRI. For treatment of several intractable autoimmune diseases (e.g., rheumatoid arthritis), where inflammatory cytokines are involved in disease progression, anti-inflammatory cytokine antagonist is now available. Hence, there is great potential of anti-inflammatory cytokine antagonist for therapeutic use of spinal cord IRI. We here review the mediators and several possibilities of treatment in spinal cord IRI.

Background. To describe the clinical characteristics of the patients who suffered from relapse after conventional irradiation for nasopharyngeal carcinoma (NPC). Methods. Three hundred and fifty-one consecutive patients with first-time recurrent NPC between January 1999 and July 2005 were included. The patients’ clinical data were reviewed, including recurrent interval time, symptoms, signs, imaging characteristics, pathologic features, and restaging. Results. The median interval of relapse was 26.0 months. The most common symptoms in symptomatic patients were nasal bloody discharge (37.9%) and headache (31.1%). Local recurrence alone accounted for 73.5%. Most patients were restaged as stage III (23.1%) and stage IV (51.1%). Subgroup analysis suggested a significantly higher proportion of the long-latent relapses originated from early primary. A series of postreirradiation complications were more frequent in patients with longer latency at reception. Conclusions. Most recurrent nasopharyngeal carcinoma is advanced disease. Patients with different recurrent interval time show different nature behavior.

Background: Septic shock is a common systemic inflammatory response syndrome for critical patients in the intensive care unit. Ulinastatin is currently used for the treatment of septic shock. Our study sought to evaluate the efficacy and safety of ulinastatin in the treatment of septic shock patients. Methods: Three English databases (Embase, Medline, and Cochrane Library) and four Chinese databases (China National Knowledge Infrastructure, Wanfang data, SinoMed, and VIP) were searched for published randomized controlled trials. Stata 16.0 software was used to conduct the meta-analysis. Results: A total of 48 articles were included (Chinese article 47, 1 in English). The results show that the treatment of ulinastatin could reduce mortality (risk ratio = 0.63, 95% confidence interval (CI) (0.55, 0.72)), multiple organ dysfunction syndrome (risk ratio = 0.6, 95% CI (0.53, 0.68)), length of intensive care unit stay (mean difference (MD) = -3.92, 95% CI (-4.65, -3.18)), length of hospital stay (MD = -4.39, 95% CI (-6.63, -2.15)) and decrease Acute Physiology and Chronic Health Evaluation II score (MD = -4.55, 95% CI (-5.63, -3.47)) and Sequential Organ Failure Assessment score (MD = -2.02, 95% CI (-2.59, -1.44)) with P < 0.001. Moreover, it lowers TNF-a (standardized mean difference (SMD) = -1.78, 95% CI (-2.24, -1.32)), Interleukin-6 (SMD = -1.17, 95% CI (-1.55, -0.8)), C reactive protein (SMD = -1.49, 95% CI (-1.99, -0.99)), hypersensitive C-reactive protein (SMD = -1.9, 95% CI (-2.87, -0.94)) and procalcitonin (SMD = -0.89, 95% CI (-1.12, -0.67)) levels in the body. Conclusions: Available evidence shows that ulinastatin reduces case mortality rate, multiple organ dysfunction syndrome, length of intensive care unit stay, and length of hospital stay and decreases Acute Physiology and Chronic Health Evaluation II score and Sequential Organ Failure Assessment score. Moreover, it also lowers TNF-a, Interleukin-6, C reactive protein, hypersensitive C-reactive protein, and procalcitonin levels in the body. [ABSTRACT FROM AUTHOR]

Abstract Background There is currently a lack of comprehensive evidence regarding the correlation between Alternate Mediterranean Diet (AMED) and the survival of patients with ovarian cancer (OC). This prospective cohort study first assessed the association of AMED, not only pre-diagnosis and post-diagnosis but also the change from pre-diagnosis to post-diagnosis with OC survival. Methods A total of 560 OC patients were included in the study, and their dietary intake was assessed using a reliable 111-item food frequency questionnaire. The overall survival (OS) of the patients was monitored through active follow-up and review of medical records until February 16th, 2023. Cox proportional hazard regression models were utilized to compute the hazard ratios (HRs) and their corresponding 95% confidence intervals (CIs). Results Out of the total 560 patients with OC, 211 (37.68%) succumbed during a median follow-up period of 44.40 months (interquartile range: 26.97–61.37). Comparative analysis indicated a significant association between the highest tertiles of pre-diagnosis (HR = 0.59; 95% CI 0.38–0.90; P trend