Interferon inducible transmembrane proteins (IFITMs) are one of several IFN-stimulated genes (ISGs) that restrict entry of enveloped viruses, including flaviviruses, filoviruses and retroviruses. It ...has been recently reported that in U87 glioblastoma cells IFITM proteins inhibit HIV-1 entry in a co-receptor-dependent manner, that is, IFITM1 is more inhibitory on CCR5 tropic HIV-1 whereas IFITM2/3 confers a greater suppression of CXCR4 counterparts. However, how entry of HIV-1 with distinct co-receptor usage is modulated by different IFITM orthologs in physiologically relevant CD4⁺ T cells and monocytes/macrophages has not been investigated in detail. Here, we report that overexpression of IFITM1, 2 and 3 in human CD4⁺ HuT78 cells, SupT1 cells, monocytic THP-1 cells and U87 cells expressing CD4 and co-receptor CCR5 or CXCR4, suppressed entry of CXCR4 tropic viruses NL4.3 and HXB2, CCR5 tropic viruses AD8 and JRFL, dual tropic 89.6 virus, as well as a panel of 32 transmitted founder (T/F) viruses, with a consistent order of potency, that is, IFITM3 > IFITM2 > IFITM1. Consistent with previous reports, we found that some CCR5-using HIV-1 isolates, such as AD8 and JRFL, were relatively resistant to inhibition by IFITM2 and IFITM3, although the effect can be cell-type dependent. However, in no case have we observed that IFITM1 had a stronger inhibition on entry of any HIV-1 strains tested, including those of CCR5-using T/Fs. We knocked down the endogenous IFITMs in peripheral blood mononuclear cells (PBMCs) and purified CD4⁺ T cells and observed that, while this treatment did greatly enhance the multiple-round of HIV-1 replication but had modest effect to rescue the single-round HIV-1 infection, reinforcing our previous conclusion that the predominant effect of IFITMs on HIV-1 infection is in viral producer cells, rather than in target cells to block viral entry. Overall, our results argue against the idea that IFITM proteins distinguish co-receptors CCR5 and CXCR4 to inhibit entry but emphasize that the predominant role of IFITMs on HIV-1 is in producer cells that intrinsically impair the viral infectivity.
A study in rodent models showed that phytosterols protected against colon carcinogenesis, probably by inhibiting dysregulated cell cycle progression and inducing cellular apoptosis. However, ...epidemiological studies on the relationship between phytosterols and colorectal cancer risk are quite limited. The aim of this study was to investigate dietary phytosterol intake in relation to colorectal cancer risk in the Chinese population. A case-control study was conducted from July 2010 to June 2016, recruiting 1802 eligible colorectal cancer cases plus 1813 age (5-year interval) and sex frequency-matched controls. Dietary information was collected by using a validated FFQ. The OR and 95 % CI of colorectal cancer risk were assessed by multivariable logistic regression models. A higher total intake of phytosterols was found to be associated with a 50 % reduction in colorectal cancer risk. After adjusting for various confounders, the OR of the highest quartile intake compared with the lowest quartile intake was 0·50 (95 % CI 0·41, 0·61, P trend<0·01) for total phytosterols. An inverse association was also found between the consumption of β-sitosterol, campesterol, campestanol and colorectal cancer risk. However, stigmasterol intake was related to an increased risk of colorectal cancer. No statistically significant association was found between β-sitostanol and colorectal cancer risk. Stratified analysis by sex showed that the positive association of stigmasterol intake with colorectal cancer risk was found only in women. These data indicated that the consumption of total phytosterols, β-sitosterol, campesterol and campestanol is inversely associated with colorectal cancer risk in a Chinese population.
Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart disease in clinical practice. It is mainly due to cardiovascular hypoplasia during embryonic development. The study aimed to ...find the etiology of TOF.
Through the mRNA expression profile analysis of the GSE35776 dataset, differentially expressed genes (DEGs) were found, and the functional analysis and protein-protein interaction (PPI) network analysis were then performed on DEGs. Likewise, the hub genes and functional clusters of DEGs were analyzed using the PPI network. Differentially expressed miRNAs were analyzed from the GSE35490 dataset, followed by miRNet predicted transcription factors (TFs) and target genes. The key TF-miRNA-gene interaction mechanism was explored through the found significant difference between genes and target genes.
A total of 191 differentially expressed genes and 57 differentially expressed miRNAs were identified. The main mechanisms involved in TOF were mitochondria-related and energy metabolism- related molecules and pathways in GO and KEGG analysis. This discovery was identical in TFs and target genes. The key miRNAs, hsa-mir-16 and hsa-mir-124, were discovered by the Venn diagram. A co-expression network with the mechanism of action centered on two miRNAs was made.
Hsa-mir-16 and hsa-mir-124 are the key miRNAs of TOF, which mainly regulate the expression of NT5DC1, ECHDC1, HSDL2, FCHO2, and ACAA2 involved in the conversion of ATP in the mitochondria and the metabolic rate of fatty acids (FA). Our research provides key molecules and pathways into the etiology of TOF, which can be used as therapeutic targets.
Characterized by scarce water resources and fragile ecosystems, Northwest China (NWC) has experienced a climate shift from warm-dry to warm-wet conditions since the 1980s that has garnered extensive ...concern in recent years. In this study, the variability in extreme precipitation (EP) during 1961–2016 in different climate zones of NWC and the possible mechanisms for this variation are investigated. The results show that the EP trends significantly increased in most of the westerly zone (WZ) and plateau zone (PZ), while the EP trends did not significantly decrease in the monsoon zone (MZ). The start dates of extreme precipitation (SDEP) and end dates of extreme precipitation (EDEP) advanced and were postponed, respectively, in the WZ and PZ, while the opposite occurred in the MZ. Summer atmospheric circulation, water vapor transport, and atmospheric instability over NWC varied greatly with the interdecadal shift in EP before and after 1986. During 1986–2016, upper-level divergence and lower-level convergence occurred in the MZ and PZ, which strengthened ascending flow. In addition, the summer water vapor and atmospheric instability increased in the WZ and PZ. These characteristics created favorable conditions for increased occurrences of EP in the WZ and PZ in summer. Conversely, the upper-level convergence and lower-level divergence in the MZ strengthened descending flow. Decreases in summer water vapor and atmospheric instability occurred in the MZ after 1986. Hence, the environmental conditions in the MZ may have prevented the occurrence and development of EP in summer during 1986–2016.
Coprescribing of clopidogrel and other drugs is common. Available reviews have addressed the drug-drug interactions (DDIs) when clopidogrel is as an object drug, or focused on combination use of ...clopidogrel and a special class of drugs. Clinicians may still be ignorant of those DDIs when clopidogrel is a precipitant drug, the factors determining the degree of DDIs, and corresponding risk management.
A literature search was performed using PubMed, MEDLINE, Web of Science, and the Cochrane Library to analyze the pharmacokinetic DDIs of clopidogrel and new P2Y12 receptor inhibitors.
Clopidogrel affects the pharmacokinetics of cerivastatin, repaglinide, ferulic acid, sibutramine, efavirenz, and omeprazole. Low efficacy of clopidogrel is anticipated in the presence of omeprazole, esomeprazole, morphine, grapefruit juice, scutellarin, fluoxetine, azole antifungals, calcium channel blockers, sulfonylureas, and ritonavir. Augmented antiplatelet effects are anticipated when clopidogrel is coprescribed with aspirin, curcumin, cyclosporin, St John's wort, rifampicin, and angiotensin-converting enzyme inhibitors. The factors determining the degree of DDIs with clopidogrel include genetic status (eg, cytochrome P540 CYP2B6*6, CYP2C19 polymorphism, CYP3A5*3, CYP3A4*1G, and CYP1A2-163C.A), species differences, and dose strength. The DDI risk does not exhibit a class effect, eg, the effects of clopidogrel on cerivastatin versus other statins, the effects of proton pump inhibitors on clopidogrel (omeprazole, esomeprazole versus pantoprazole, rabeprazole), the effects of rifampicin on clopidogrel versus ticagrelor and prasugrel, and the effects of calcium channel blockers on clopidogrel (amlodipine versus P-glycoprotein-inhibiting calcium channel blockers). The mechanism of the DDIs with clopidogrel involves modulating CYP enzymes (eg, CYP2B6, CYP2C8, CYP2C19, and CYP3A4), paraoxonase-1, hepatic carboxylesterase 1, P-glycoprotein, and organic anion transporter family member 1B1.
Effective and safe clopidogrel combination therapy can be achieved by increasing the awareness of potential changes in efficacy and toxicity, rationally selecting alternatives, tailoring drug therapy based on genotype, checking the appropriateness of physician orders, and performing therapeutic monitoring.
Epithelial ovarian cancer (EOC) is one of the most malignant gynecological tumors worldwide. Deregulation of long non-coding RNAs (lncRNAs) has been implicated in various oncogenic processes in ...multiple cancers. In this study, we aim to identify and characterize clinically relevant lncRNA deregulation in EOC.
LncRNAs, mRNAs and miRNAs were profiled using expression microarrays and validated using reverse transcription quantitative PCR in EOC cells and tissues. siRNAs targeting either HOXD-AS1 or PIK3R3 together with miR-186-5p inhibitors were used to modulate endogenous target expression in EOC cell lines in vitro. In vitro wound healing assay, trans-well assay, Western-blot assay,and Dual-luciferase reporter assay were used to explore the biological roles and molecular function underlying HOXD-AS1 in the EOC cells. Progression-free survival (PFS) and overall survival (OS) were statistically analyzed by Kaplan-Meier method test.
HOXD-AS1 was found to be significantly over-expressed in EOC tumors. High HOXD-AS1 expression significantly correlated with poorer PFS and OS of EOC patients. Multivariate Cox proportional hazards modeling indicated that HOXD-AS1 was an independent risk predictor of EOC patients (HR = 1.92, p = 0.004). SiRNA inhibition of HOXD-AS1 reduced cell migration, invasion, and epithelial-mesenchymal transition (EMT) in EOC cells in vitro by preventing HOXD-AS1 directly binding to miR-186-5p, and resulting in down-regulating of PIK3R3. The novel HOXD-AS1/miR-186-5p/PIK3R3 pathway was clinically relevant as we observed a significantly inverse correlation between HOXD-AS1/miR-186-5p and between miR-186-5p/PIK3R3 in an independent cohort of 200 EOC tissues.
HOXD-AS1/miR-186-5p/PIK3R3 is a novel pathway to promote cell migration, invasion, and EMT in EOC.
Interferon-inducible transmembrane proteins (IFITMs) inhibit a broad spectrum of viruses, including HIV-1. IFITM proteins deter HIV-1 entry when expressed in target cells and also impair HIV-1 ...infectivity when expressed in virus producer cells. However, little is known about how viruses resist IFITM inhibition. In this study, we have investigated the susceptibilities of different primary isolates of HIV-1 to the inhibition of viral infectivity by IFITMs. Our results demonstrate that the infectivity of different HIV-1 primary isolates, including transmitted founder viruses, is diminished by IFITM3 to various levels, with strain AD8-1 exhibiting strong resistance. Further mutagenesis studies revealed that HIV-1 Env, and the V3 loop sequence in particular, determines the extent of inhibition of viral infectivity by IFITM3. IFITM3-sensitive Env proteins are also more susceptible to neutralization by soluble CD4 or the 17b antibody than are IFITM3-resistant Env proteins. Together, data from our study suggest that the propensity of HIV-1 Env to sample CD4-bound-like conformations modulates viral sensitivity to IFITM3 inhibition.
Results of our study have revealed the key features of the HIV-1 envelope protein that are associated with viral resistance to the IFITM3 protein. IFITM proteins are important effectors in interferon-mediated antiviral defense. A variety of viruses are inhibited by IFITMs at the virus entry step. Although it is known that envelope proteins of several different viruses resist IFITM inhibition, the detailed mechanisms are not fully understood. Taking advantage of the fact that envelope proteins of different HIV-1 strains exhibit different degrees of resistance to IFITM3 and that these HIV-1 envelope proteins share the same domain structure and similar sequences, we performed mutagenesis studies and determined the key role of the V3 loop in this viral resistance phenotype. We were also able to associate viral resistance to IFITM3 inhibition with the susceptibility of HIV-1 to inhibition by soluble CD4 and the 17b antibody that recognizes CD4-binding-induced epitopes.
Leaf chlorophyll content (LCC) provides valuable information about plant physiology. Most of the published chlorophyll vegetation indices at the leaf level have been based on the spectral ...characteristics of the adaxial leaf surface, thus, they are not appropriate for estimating LCC when both the adaxial and abaxial leaf surfaces influence the spectral reflectance. We attempted to address this challenge by measuring the spectral reflectance of the adaxial and abaxial leaf surfaces of several plant species at different growth stages using a portable field spectroradiometer. The relationships between more than 30 published reflectance indices with LCC were analyzed to determine which index estimated LCC most effectively. Additionally, since the relationships determined on one set of samples might have poor predictive performances when applied to other samples, a robust wavelength region is required to render the spectral index generally applicable, regardless of the leaf surface or plant species.
The Modified Datt (MDATT) index, which is the ratio of reflectance difference defined as (R
- R
)/(R
- R
), exhibited the strongest correlation (R
= 0.856, RMSE = 6.872 μg/cm
), with LCC of all the indices tested when all the leaf samples from the adaxial and abaxial surfaces were combined. The optimal wavelength regions, which were derived from the contour maps of R
between the MDATT index and LCC for the datasets of one side or both leaf surfaces of each plant species and their intersection, indicated that the red-edge to near-infrared wavelength (723-885 nm) was optimal for λ
, while the red-edge region (697-771 nm) was optimal for λ
and λ
. In these optimal wavelength regions, when the MDATT index was used to estimate LCC, an R
higher than 0.8 could be obtained. The correlation of the MDATT index with LCC was the same when the positions of λ
and λ
were exchanged in the index.
MDATT is proposed as an optimal index for the remote estimation of vegetation chlorophyll content across several plant species in different growth stages when reflectance from both leaf surfaces is considered. The red-edge to near-infrared wavelength (723-885 nm) for λ
, as well as the red-edge region (697-771 nm) for λ
or λ
, are considered to be the most robust for constructing the MDATT index for estimating LCC, regardless of the leaf surface or plant species.
The purpose of this study was to analyse the clinical characteristics of patients with severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) PCR re-positivity after recovering from coronavirus ...disease 2019 (COVID-19). Patients (n = 1391) from Guangzhou, China, who had recovered from COVID-19 were recruited between 7 September 2021 and 11 March 2022. Data on epidemiology, symptoms, laboratory test results and treatment were analysed. In this study, 42.7% of recovered patients had re-positive result. Most re-positive patients were asymptomatic, did not have severe comorbidities, and were not contagious. The re-positivity rate was 39%, 46%, 11% and 25% in patients who had received inactivated, mRNA, adenovirus vector and recombinant subunit vaccines, respectively. Seven independent risk factors for testing re-positive were identified, and a predictive model was constructed using these variables. The predictors of re-positivity were COVID-19 vaccination status, previous SARs-CoV-12 infection prior to the most recent episode, renal function, SARS-CoV-2 IgG and IgM antibody levels and white blood cell count. The predictive model could benefit the control of the spread of COVID-19.
Abstract
Parkinson’s disease (PD) is a multi-system neurodegenerative disorder. Patients with PD often suffer chronic pain. In the present study, we investigated motor, sensory and emotional changes ...in three different PD mice models. We found that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treatment caused significant changes in all measurements. Mechanical hypersensitivity of PD model induced by MPTP peaked at 3 days and persisted for at least 14 days. Using Fos transgenic mice, we found that neurons in the anterior cingulate cortex (ACC) were activated after MPTP treatment. Inhibiting ACC by bilateral microinjection of muscimol significantly reduced mechanical hypersensitivity and anxiety-like responses. By contrast, MPTP induced motor deficit was not affected, indicating ACC activity is mostly responsible for sensory and emotional changes. We also investigated excitatory synaptic transmission and plasticity using brain slices of MPTP treated animals. While L-LTP was blocked or significantly reduced. E-LTP was not significantly affected in slices of MPTP treated animals. LTD induced by repetitive stimulation was not affected. Furthermore, we found that paired-pulse facilitation and spontaneous release of glutamate were also altered in MPTP treated animals, suggesting presynaptic enhancement of excitatory transmission in PD. Our results suggest that ACC synaptic transmission is enhanced in the animal model of PD, and cortical excitation may play important roles in PD related pain and anxiety.
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