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.
MicroRNAs have been shown to play an important role in normal hematopoisis and leukemogenesis. Here, we report function and mechanisms of miR-181 family in myeloid differentiation and acute myeloid ...leukemia (AML). The aberrant overexpression of all the miR-181 family members (miR-181a/b/c/d) was detected in French-American-British M1, M2 and M3 subtypes of adult AML patients. By conducting gain- and loss-of-function experiments, we demonstrated that miR-181a inhibits granulocytic and macrophage-like differentiation of HL-60 cells and CD34+ hematopoietic stem/progenitor cells (HSPCs) by directly targeting and downregulating the expression of PRKCD (which then affected the PRKCD-P38-C/EBPα pathway), CTDSPL (which then affected the phosphorylation of retinoblastoma protein) and CAMKK1. The three genes were also demonstrated to be the targets of miR-181b, miR-181c and miR-181d, respectively. Significantly decreases in the expression levels of the target proteins were detected in AML patients. Inhibition of the expression of miR-181 family members owing to Lenti-miRZip-181a infection in bone marrow blasts of AML patients increased target protein expression levels and partially reversed myeloid differentiation blockage. In the mice implanted with AML CD34+ HSPCs, expression inhibition of the miR-181 family by Lenti-miRZip-181a injection improved myeloid differentiation, inhibited engraftment and infiltration of the leukemic CD34+ cells into the bone marrow and spleen, and released leukemic symptoms. In conclusion, our findings revealed new mechanism of miR-181 family in normal hematopoiesis and AML development, and suggested that expression inhibition of the miR-181 family could provide a new strategy for AML therapy.
Resveratrol (RES) is a naturally occurring and effective drug for tumor prevention and treatment. However, its low levels of aqueous solubility, stability, and poor bioavailability limit its ...application, especially when used as a free drug. In this study, RES was loaded into peptide and sucrose liposomes (PSL) to enhance the physico-chemical properties of RES and exploit RES delivery mediated by liposomes to effectively treat breast cancer. RES loaded PSL (the complex: PSL@RES) were stable, had a good RES encapsulation efficiency, and prolonged RES-release
in vitro
. PSL@RES was exceptionally efficient for inhibiting the growth of cancer cells, as the IC
50
of PSL@RES in MCF-7 cells was found to be only 20.89 μmol L
−1
. The therapeutic efficacy of PSL@RES was evaluated in mice bearing breast cancer. The results showed that PSL@RES at a dosage of 5 mg kg
−1
was more effective than 10 mg kg
−1
free RES, and PSL@RES inhibited tumor growth completely at a dosage of 10 mg kg
−1
. PSL@RES induced apoptosis in breast tumor by upregulation of p53 expression. This then downregulated Bcl-2 and upregulated Bax, thereby inducing Caspase-3 activation. More importantly, encapsulation of RES within peptide liposomes greatly reduced the toxicity of free RES to mice. Overall, the simple formulation of liposomal nanocarriers of RES developed in this study produces satisfactory outcomes to encourage further applications of liposomal carriers for the treatment of breast cancer.
RES encapsulated in tri-peptide liposome led to obvious apoptosis of tumor cells and great inhibition of tumors at low doses, and significantly decreased the toxicity of RES to mice.
This study aimed to explore the effect and mechanism of chondrocyte apoptosis on the chemotaxis of osteoclast precursors (OCPs) during bone destruction.
The relationship between cartilage and bone ...destruction was verified with a rat temporomandibular joint osteoarthritis (TMJOA) model. The pan-caspase inhibitor Z-VAD-FMK (ZVAD) was applied to confirm the chemotactic effect of chondrocyte apoptosis on OCPs. Synthesis and release of the key chemokine CX3CL1 in apoptotic and non-apoptotic chondrocytes was assessed with IHC, IF, WB, and ELISA. The function of CX3CL1-CX3CR1 axis in the chemotaxis of OCPs was examined by CX3XR1 inhibitor AZD8797 (AZD) and si-CX3CL1. The regulatory effect of p38 MAPK on CX3CL1 release was verified by p38 inhibitor PH-797804.
A temporal and spatial association between cartilage degradation and bone resorption was found in the TMJOA model. The caspase-dependent chondrocyte apoptosis promoted chemotaxis of OCPs, which can be restrained by ZVAD. CX3CL1 was significantly upregulated when chondrocytes underwent apoptosis, and it played a critical role in the recruitment of OCPs, blockage of CX3CL1-CX3CR1 axis resulted in less bone resorption in TMJOA. P38 MAPK was activated in apoptotic chondrocytes, and had a regulatory effect on the synthesis and release of CX3CL1. After inhibition of p38 by PH-797804, the chemotactic effect of apoptotic chondrocytes on OCPs was limited.
This study indicates that apoptosis of chondrocytes in TMJOA enhances chemotaxis of OCPs toward osteoclast precursors through upregulation of the p38-CX3CL1 axis, thereby promoting the activation of local osteoclasts.
Employees perceive illegitimate tasks as inappropriate assignments because such tasks are beyond what they expect to do in any given job position. Extant literature indicates that, in addition to ...creating psychological strain and reducing well-being, illegitimate task assignments can result in counterproductive work behavior (CWB). This study extends the literature by examining whether illegitimate tasks may lead to two specific forms of CWB targeting organizations: destructive voice and time theft. To understand how and when this happens, we investigate the mediating role of moral disengagement and the moderating role of psychological entitlement. Survey results based on 258 supervisor–subordinate dyads in China reveal that illegitimate tasks are positively related to destructive voice and time theft through moral disengagement. Furthermore, psychological entitlement strengthens the positive relationship between illegitimate tasks and moral disengagement and the indirect effect of illegitimate tasks on destructive voice and time theft. Overall, the findings provide insightful theoretical and managerial implications for research related to illegitimate tasks and CWB.
The aim of this study was to comparatively evaluate the indications and treatment outcomes of two transcutaneous approaches for the removal of impacted parotid stones. Sixty-eight consecutive ...patients with impacted parotid stones underwent endoscopy-assisted lithotomy via a direct mini-incision or a peri-auricular flap. Clinical safety and outcomes were evaluated. Complete stone extraction was achieved in all patients. In the mini-incision group (52 patients), the stones were in the middle third of the main duct in 31 patients, at the hilum in 16, and in the intraglandular duct in five. In the flap group (16 patients), they were in the middle third of the main duct in one patient, at the hilum in seven, and in the intraglandular duct in eight. Salivary fistula occurred in five mini-incision group patients (9.6%) and four flap group patients (25%). The clinical outcome in the mini-incision group (47 patients, median 25 months of follow-up) was good in 28 patients, fair in 13, and poor in six (12.8%). The clinical outcome in the flap group (16 patients, median 84 months of follow-up) was good in nine patients, fair in five, and poor in two (12.5%). The direct mini-incision approach was found to be safe and effective for impacted stones in the middle third, hilum, and proximal third of the main duct, while the peri-auricular approach would be best reserved for deeper intraglandular stones.
There is a growing awareness that complex 3-dimensional (3D) organs are not well represented by monolayers of a single cell type - the standard format for many drug screens. To address this ...deficiency, and with the goal of improving screens so that drugs with good efficacy and low toxicity can be identified, microphysiological systems (MPS) are being developed that better capture the complexity of in vivo physiology. We have previously described an organ-on-a-chip platform that incorporates perfused microvessels, such that survival of the surrounding tissue is entirely dependent on delivery of nutrients through the vessels. Here we describe an arrayed version of the platform that incorporates multiple vascularized micro-organs (VMOs) on a 96-well plate. Each VMO is independently-addressable and flow through the micro-organ is driven by hydrostatic pressure. The platform is easy to use, requires no external pumps or valves, and is highly reproducible. As a proof-of-concept we have created arrayed vascularized micro tumors (VMTs) and used these in a blinded screen to assay a small library of compounds, including FDA-approved anti-cancer drugs, and successfully identified both anti-angiogenic and anti-tumor drugs. This 3D platform is suitable for efficacy/toxicity screening against multiple tissues in a more physiological environment than previously possible.
This paper reports a microfluidic system that enables the characterization of tumor cell electrical properties where cells were aspirated through a constriction channel (cross-section area smaller ...than that of biological cells) with cellular impedance profiles measured and translated to specific membrane capacitance (Cspecific membrane) and cytoplasm conductivity (σcytoplasm). Two batches of H1299 cells were quantified by the microfluidic platform with different constriction channel cross-section areas, recording no differences with statistical significance (p<0.001) in both Cspecific membrane (1.63±0.52 vs. 1.65±0.43μF/cm2) and σcytoplasm (0.90±0.19 vs. 0.92±0.15S/m), and thus confirming the reliability of the microfluidic platform. For paired high- and low-metastatic carcinoma strains 95D (ncell=537) and 95C cells (ncell=486), significant differences in both Cspecific membrane (2.00±0.43 vs. 1.62±0.39μF/cm2) and σcytoplasm (0.88±0.46 vs. 1.25±0.35S/m) were observed. Statistically significant difference only in Cspecific membrane (2.00±0.43 vs. 1.58±0.30μF/cm2) was observed for 95D cells (ncell=537) and 95D CCNY-KD cells with single oncogene CCNY down regulation (ncell=479, CCNY is a membrane-associated protein). In addition, statistically significant difference only in σcytoplasm (0.73±0.17 vs. 1.01±0.17S/m) was observed for A549 cells (ncell=487) and A549 CypA-KD cells with single oncogene CypA down regulation (ncell=597, CypA is a cytosolic protein). These results validated the developed microfluidic platform for Cspecific membrane and σcytoplasm quantification and confirmed the feasibility of using Cspecific membrane and σcytoplasm for tumor cell classification.
•A microfluidic platform to quantify tumor cell electrical properties was developed.•Electrical differences from paired high and low-metastatic cell lines were observed.•Electrical differences with/without single oncogene regulation were observed.•Correlation between Cspecific membrane and membrane protein expression was located.•Correlation between σcytoplasm and cytosolic protein expression was located.
Summary
Background
Inherited epidermodysplasia verruciformis (EV) is a rare skin disorder characterized by susceptibility to specific types of human papilloma virus (HPV) and is strongly associated ...with skin carcinomas. Inactivating mutations in EVER1/EVER2 account for most cases of EV. However, more phenotypes related to but distinct from EV have been reported with an immunodeficiency state but without EVER1/EVER2 mutation, and the genetic basis for these atypical EV cases is poorly understood.
Objectives
To identify the causative gene responsible for three siblings affected by atypical EV but without EVER1/EVER2 mutation.
Methods
Whole‐exome sequencing followed by Sanger sequencing was performed to identify the gene responsible for the patients with atypical EV enrolled in our study.
Results
A homozygous splicing mutation was detected in LCK (c.188‐2A>G). This mutation resulted in an exon 3 deletion T lymphocyte‐specific protein tyrosine kinase isoform, which further led to frameshift mutation and subsequent mRNA decay.
Conclusions
We demonstrate a novel mutation in LCK in a family affected by atypical EV with T‐cell defects, HPV infection and virus‐induced malignancy, providing new clues in the understanding of host defences against HPV and better genetic counselling of patients with the EV phenotype.
What's already known about this topic?
Epidermodysplasia verruciformis (EV) is an unusual genodermatosis characterized by an increased susceptibility to β‐human papillomavirus and is associated with a high risk of skin carcinoma.
Inactivating mutations in EVER1/EVER2 account for most cases of EV.
What does this study add?
Our study suggests an association between a novel splicing mutation in LCK and EV susceptibility.
What is the translational message?
Patients with EV should be tested for T lymphocyte‐specific protein tyrosine kinase deficiency and T‐cell function, which will help guide treatment.
Linked Comment: Uitto and Vahidnezhad. Br J Dermatol 2016; 175:1138–1139.
The aim of this study was to investigate the prognostic significance of the serum γ-glutamyltransferase (γ-GT)-to-prealbumin ratio (GPR) and whether combining this ratio with other parameters can ...lead to an improved prognostic value for patients with hepatocellular carcinoma (HCC) undergoing transcatheter arterial chemoembolization (TACE) combined with local ablation therapy.
A total of 235 HCC patients who were treated with combined therapies were retrospectively analyzed. The demographic data and clinicopathological data were collected. A fibrinogen (Fib)-GPR score of 2 was assigned to patients with elevated Fib and GPR values, and a score of 1 or 0 was assigned to patients with one or neither of these two markers, respectively. In addition, an N-score of 2 was assigned to patients with low neutrophil and high GPR values, and a score of 1 or 0 was assigned to patients with one or neither of these two markers, respectively. The optimal cutoff values and prognostic roles of GPR and other markers were identified according to the time-dependent receiver operating characteristic (ROC) curves and Youden's index.
Multiple tumors, high levels of α-fetoprotein (AFP) and Fib, as well as a high GPR, were found to be independent risk factors in recurrent patients, while multiple tumors, a low neutrophil count, and a high GPR were associated with reduced overall survival (OS) in patients with HCC who received combined therapies. Patients with a Fib-GPR score of 2 and N-GPR score of 2 had poor recurrence-free survival (RFS) and OS, respectively.
Fib-GPR and N-GPR scores may be helpful in predicting both recurrence and the prognosis of HCC patients, thereby assisting in the process to make a true clinical decision and optimize therapeutic options.
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