Understanding how flowering phenology responds to warming and cooling (i.e., symmetric or asymmetric response) is needed to predict the response of flowering phenology to future climate change that ...will happen with the occurrence of warm and cold years superimposed upon a long-term trend. A three-year reciprocal translocation experiment was performed along an elevation gradient from 3200 m to 3800 m in the Tibetan Plateau for six alpine plants. Transplanting to lower elevation (warming) advanced the first flowering date (FFD) and transplanting to higher elevation (cooling) had the opposite effect. The FFD of early spring flowering plants (ESF) was four times less sensitive to warming than to cooling (by −2.1 d/°C and 8.4 d/°C, respectively), while midsummer flowering plants (MSF) were about twice as sensitive to warming than to cooling (−8.0 d/°C and 4.9 d/°C, respectively). Compared with pooled warming and cooling data, warming alone significantly underpredicted 3.1 d/°C for ESF and overestimated 1.7 d/°C for MSF. These results suggest that future empirical and experimental studies should consider nonlinear temperature responses that can cause such warming-cooling asymmetries as well as differing life strategies (ESF vs. MSF) among plant species.
The measurement of the energy spectrum of cosmic ray helium nuclei from 70 GeV to 80 TeV using 4.5 years of data recorded by the Dark Matter Particle Explorer (DAMPE) is reported in this work. A ...hardening of the spectrum is observed at an energy of about 1.3 TeV, similar to previous observations. In addition, a spectral softening at about 34 TeV is revealed for the first time with large statistics and well controlled systematic uncertainties, with an overall significance of 4.3σ. The DAMPE spectral measurements of both cosmic protons and helium nuclei suggest a particle charge dependent softening energy, although with current uncertainties a dependence on the number of nucleons cannot be ruled out.
Aims
The aim of this study was to determine the effects of unsaturated fatty acids on clinical plasmids.
Methods and Results
Two unsaturated fatty acids, linoleic acid (LA) and α‐linolenic acid (ALA) ...at final concentration 0, 0·03, 0·3 and 3 mmol l−1, respectively, were used to assess the effects on conjugative transfer of a mcr‐1‐harbouring plasmid pCSZ4 (IncX4) in conjugation experiment. The inhibitory mechanisms were analysed by molecular docking and the gene expression of virB11 was quantitated by qRT‐PCR. Target plasmid diversity was carried out by TrwD/VirB11 homology protein sequence prediction analysis. Our results showed that LA and ALA inhibit plasmid pCSZ4 transfer by binding to the amino acid residues (Phe124 and Thr125) of VirB11 with dose‐dependent effects. The expression levels of virB11 gene were also significantly inhibited by LA and ALA treatment. Protein homology analysis revealed a wide distribution of TrwD/VirB11‐like genes among over 37 classes of plasmids originated from both Gram‐negative and Gram‐positive bacteria.
Conclusions
This study demonstrates representing a diversity of plasmids that may be potentially inhibited by unsaturated fatty acids.
Significance and Impact of the Study
Our work reported here provides additional support for application of curbing the spread of multiple plasmids by unsaturated fatty acids.
Summary
What is known and Objective: Tacrolimus (TAC) is metabolized mainly by the CYP3A subfamily and extruded into the intestine by P‐glycoprotein, which is encoded by the ABCB1 gene. Several ...studies have suggested that the CYP3A5*3 genotype influenced the pharmacokinetics (PK) of TAC. The CYP3A4*18B and CYP3A5*3 alleles are clinically important in Chinese subjects because of their relatively high frequency. The present study aimed at evaluating the effects of ABCB1 (C1236T‐G2677T/A‐C3435T), CYP3A4*18B and CYP3A5*3 genetic polymorphisms on TAC PK in healthy Chinese subjects.
Methods: Data were obtained from a comparative bioavailability study of oral TAC formulations (n = 22). TAC whole blood concentrations were measured by LC‐MS/MS. Genetic polymorphisms were determined using a direct sequencing method. Nonlinear mixed‐effects modelling (NONMEM) was performed to assess the effect of genotypes and demographics on TAC PKs.
Results and Discussion: Both CYP3A4*18B and CYP3A5*3 polymorphisms affected the TAC PK, whereas ABCB1 genetic polymorphisms and other demographic characteristics did not. The combined genotypes of CYP3A4*18B and CYP3A5*3 had a greater impact than either genotype alone, and they were estimated to account for 28·4% of the inter‐subject variability of apparent clearance (CL/F) by NONMEM. The CL/F in subjects with CYP3A4*1/*1‐CYP3A5*3/*3 was 10·3 L/h and was 48·5% in those not carrying CYP3A4*1/*1‐CYP3A5*3/*3.
What is new and Conclusion: This is the first study to extensively explore the influence of CYP3A4*18B, CYP3A5*3 and ABCB1 genetic polymorphisms on TAC PK in healthy Chinese subjects. The results demonstrated that subjects with a combined genotype of CYP3A4*1/*1‐CYP3A5*3/*3 may require lower TAC doses to achieve target concentration levels and further investigation is needed in larger populations to confirm the clinical benefits.
Liver kinase B1 (LKB1) is mutationally inactivated in Peutz-Jeghers syndrome and in a variety of cancers including human papillomavirus (HPV)-caused cervical cancer. However, the significance of LKB1 ...mutations in cervical cancer initiation and progress has not been examined. Herein, we demonstrated that, in mouse embryonic fibroblasts, loss of LKB1 and transduction of HPV16 E6/E7 had an additive effect on constraining cell senescence while promoting cell proliferation and increasing glucose consumption, lactate production and ATP generation. Knockdown of LKB1 increased and ectopic expression of LKB1 decreased glycolysis, anchorage-independent cell growth, and cell migration and invasion in HPV-transformed cells. In the tumorigenesis and lung metastasis model in syngeneic mice, depletion of LKB1 markedly increased tumor metastatic colonies in lungs without affecting subcutaneous tumor growth. We showed that HPV16 E6/E7 enhanced the expression of hexokinase-ll (HK-II) in the glycolytic pathway through elevated c-MYC. Ectopic LKB1 reduced HK-II along with glycolysis. The inverse relationship between HK-II and LKB1 was also observed in normal and HPV-associated cervical lesions. We propose that LKB1 acts as a safeguard against HPV-stimulated aerobic glycolysis and tumor progression. These findings may eventually aid in the development of therapeutic strategy for HPV-associated malignancies by targeting cell metabolism.
To elucidate the cytotoxicity mechanism of Garnoderma triterpenes, a chemoproteomic study using five purified ganoderic acids, ganoderic acid F (GAF), ganoderic acid K (GAK), ganoderic B (GAB), ...ganoderic acid D (GAD) and ganoderic acid AM1 (GAAM1) was conducted. GAF, GAK, GAB, GAD and GAAM1 treatment for 48 h inhibited the proliferation of HeLa human cervical carcinoma cells with IC
50 values of 19.5±0.6
μM, 15.1±0.5
μM, 20.3±0.4
μM, 17.3±0.3
μM, 19.8±0.7
μM, respectively. The protein expression profiles of HeLa cells treated with each ganoderic acid at dose of 15
μM for 48
h were checked using two-dimensional electrophoresis (2-DE). The possible target-related proteins of ganoderic acids, i.e. proteins with same change tendency in all five ganoderic acids-treated groups compared with control, were identified using MALDI-TOF MS/MS. Twelve proteins including human interleukin-17E, eukaryotic translation initiation factor 5A (eIF5A), peroxiredoxin 2, ubiquilin 2, Cu/Zn-superoxide dismutase, 14-3-3 beta/alpha, TPM4-ALK fusion oncoprotein type 2, PP2A subunit A PR65-alpha isoform, nucleobindin-1, heterogeneous nuclear ribonucleoprotein K, reticulocalbin 1 and chain A of DJ-1 protein were identified. Ganoderic acids might exert their cytotoxicity by altering proteins involved in cell proliferation and/or cell death, carcinogenosis, oxidative stress, calcium signaling and ER stress.
Abstract
Here we present a detailed study of the broadband noise in the power density spectra of the black hole X-ray binary MAXI J1820+070 during the hard state of its 2018 outburst, using Hard ...X-ray Modulation Telescope observations. The broadband noise shows two main humps, which might separately correspond to variability from a variable disk and two Comptonization regions. We fitted the two humps with multiple Lorentzian functions and studied the energy-dependent properties of each component up to 90–150 keV and their evolution with spectral changes. The lowest-frequency component is considered as the subharmonic of the quasiperiodic oscillation component and shows a different energy dependence compared with other broadband noise components. We found that although the fractional rms of all the broadband noise components mainly decreases with the energy, their rms spectra are different in shape. Above ∼20–30 keV, the characteristic frequencies of these components increase sharply with the energy, meaning that the high-energy component is more variable on short timescales. Our results suggest that the hot inner flow in MAXI J1820+070 is likely to be inhomogeneous. We propose a geometry with a truncated accretion disk and two Comptonization regions.
PDF
