The Stirling engine is deemed to play a role in the near future of power generation. However, there is a large performance difference between the real and ideal Stirling engine. The use of sinusoidal ...motion for both displacer and piston in current applications is one of the reasons for this difference as it limits heat transfer. This paper investigated the use of non-sinusoidal rise-dwell-fall-dwell (RDFD) motion on both displacer and piston to improve the performance of a real Stirling engine and compared it to the conventional sinusoidal motion crankshaft driven Stirling engine. A gamma configuration Stirling engine test rig with a data acquisition system was constructed for this investigation. Among the four flywheels with each specifically designed cam profile tested, one was with sinusoidal motion while the remaining three were non-sinusoidal for comparison. The use of non-sinusoidal RDFD cam with 135° displacer dwell improved more than 36% thermal efficiency over sinusoidal motion crankshaft Stirling engine.
The use of nanocarriers to improve the delivery and efficacy of antimetastatic agents is less explored when compared to cytotoxic agents. This study reports the entrapment of an antimetastatic Signal ...Transducer and Activator of Transcription 3 (STAT3) dimerization blocker, Stattic (S) into a chitosan-coated-poly(lactic-co-glycolic acid) (C-PLGA) nanocarrier and the improvement on the drug's physicochemical, in vitro and in vivo antimetastatic properties post entrapment.
In vitro, physicochemical properties of the Stattic-entrapped C-PLGA nanoparticles (S@C-PLGA) and Stattic-entrapped PLGA nanoparticles (S@PLGA, control) in terms of size, zeta potential, polydispersity index, drug loading, entrapment efficiency, Stattic release in different medium and cytotoxicity were firstly evaluated. The in vitro antimigration properties of the nanoparticles on breast cancer cell lines were then studied by Scratch assay and Transwell assay. Study on the in vivo antitumor efficacy and antimetastatic properties of S@C-PLGA compared to Stattic were then performed on 4T1 tumor bearing mice.
The S@C-PLGA nanoparticles (141.8 ± 2.3 nm) was hemocompatible and exhibited low Stattic release (12%) in plasma. S@C-PLGA also exhibited enhanced in vitro anti-cell migration potency (by >10-fold in MDA-MB-231 and 5-fold in 4T1 cells) and in vivo tumor growth suppression (by 33.6%) in 4T1 murine metastatic mammary tumor bearing mice when compared to that of the Stattic-treated group. Interestingly, the number of lung and liver metastatic foci was found to reduce by 50% and 56.6%, respectively, and the average size of the lung metastatic foci was reduced by 75.4% in 4T1 tumor-bearing mice treated with S@C-PLGA compared to Stattic-treated group (p < 0.001).
These findings suggest the usage of C-PLGA nanocarrier to improve the delivery and efficacy of antimetastatic agents, such as Stattic, in cancer therapy.
The vertebrate left-right axis is specified during embryogenesis by a transient organ: the left-right organizer (LRO). Species including fish, amphibians, rodents and humans deploy motile cilia in ...the LRO to break bilateral symmetry, while reptiles, birds, even-toed mammals and cetaceans are believed to have LROs without motile cilia. We searched for genes whose loss during vertebrate evolution follows this pattern and identified five genes encoding extracellular proteins, including a putative protease with hitherto unknown functions that we named ciliated left-right organizer metallopeptide (CIROP). Here, we show that CIROP is specifically expressed in ciliated LROs. In zebrafish and Xenopus, CIROP is required solely on the left side, downstream of the leftward flow, but upstream of DAND5, the first asymmetrically expressed gene. We further ascertained 21 human patients with loss-of-function CIROP mutations presenting with recessive situs anomalies. Our findings posit the existence of an ancestral genetic module that has twice disappeared during vertebrate evolution but remains essential for distinguishing left from right in humans.
The incidence of acute kidney injury (AKI) among hospitalised patients has not been well studied in Malaysia.
We conducted a prospective, multicentre study in seven hospitals in West Malaysia. All ...the adults admitted in March 2017 fulfilling Kidney Disease Improving Global Outcomes (KDIGO) criteria for AKI were included.
Of the 34,204 patients screened, 2,457 developed AKI (7.18%), 13.1% of which occurred in intensive care unit (ICU). There were 60.2% males with a mean age of 57.8 (±17.5) years. The most common comorbidities were hypertension (55.0%), diabetes (46.6%), ischaemic heart disease (15.1%) and chronic kidney disease (12.0%). The commonest causes of AKI were sepsis (41.7%), pre-renal (24.2%) and cardiorenal syndrome (10.8%). Nephrotoxin exposure was reported in 31%. At diagnosis, the proportion of AKI stages 1, 2 and 3 were 79.1%, 9.7%, 11.2%, respectively. Referral to nephrologists was reported in 16.5%. Dialysis was required in 176 (7.2%) patients and 55.6% were performed in the ICU. Acidosis (46.2%), uraemia (31.6%) and electrolyte disturbance (11.1%) were the commonest indications. Continuous renal replacement therapy (CRRT) was required in 14%. The average length of hospital stay was 9.5 days. In-hospital mortality was 16.4%. Among survivors, full and partial renal recovery was seen in 74.7% and 16.4% respectively while 8.9% failed to recover. After a mean follow-up of 13.7 months, 593 (30.2%) of survivors died and 38 (1.9%) initiated chronic dialysis. Mortality was highest among those with malignancies (Hazard Ratio, HR 2.14), chronic liver disease (HR 2.13), neurological disease (HR 1.56) and cardiovascular disease (HR 1.17).
AKI is common in hospitalised patients and is with associated high mortality during and after hospitalisation.
Abstract
An attractive approach to target intracellular macromolecular interfaces and to model putative drug interactions is to design small high-affinity proteins. Variable domains of the ...immunoglobulin heavy chain (VH domains) are ideal miniproteins, but their development has been restricted by poor intracellular stability and expression. Here we show that an autonomous and disufhide-free VH domain is suitable for intracellular studies and use it to construct a high-diversity phage display library. Using this library and affinity maturation techniques we identify VH domains with picomolar affinity against eIF4E, a protein commonly hyper-activated in cancer. We demonstrate that these molecules interact with eIF4E at the eIF4G binding site via a distinct structural pose. Intracellular overexpression of these miniproteins reduce cellular proliferation and expression of malignancy-related proteins in cancer cell lines. The linkage of high-diversity in vitro libraries with an intracellularly expressible miniprotein scaffold will facilitate the discovery of VH domains suitable for intracellular applications.
Aeromonas hydrophila can enter fish cells and exist as intracellular parasites. Phase‐contrast and confocal microscopy were used to examine morphological changes and various cytoskeletal components ...of infected fish cells. Four fish cell lines were included in this study: (1) AS, (2) BF2, (3) CHSE‐214, and (4) EPC cells. Virulent but not avirulent strains of A. hydrophila PPD 134/91 invaded fish cells, causing morphological changes, and inducing microfilament (F‐actin) rearrangement. Morphological changes were observed in all infected fish cell lines and could be classified into three different stages. In stage I, the cells became detached from each other and pointed ends were observed. In stage II, tubular cytoplasmic extensions formed at contact points connecting neighbouring cells. The monolayers formed a satellite‐like organization and became less confluent. Finally (stage III), cells were heavily infected with bacteria, and bacteria containing vacuoles occupied most of the cells. They eventually detached and lysed. Rearrangement of F‐actin was observed as local polymerization (actin clouds) in stage I and massive reorganization in stage III of infection. Actin clouds could have been induced by A. hydrophila for ‘assisted' uptake into the cells. The massive reorganization of actin in stage III may be due to products released by the bacteria and the growth of vacuoles. Pretreatment of fish cells with the microfilament inhibitors such as cytochalasins induced a similar effect. There were little if any rearrangements in intermediate and microtubule filaments during bacterial entry (stages I and II). These results suggest that A. hydrophila may bind to the surface and trigger a signal to the microfilament which then generates the force necessary for bacterial uptake.
Airgap membrane distillation (AGMD) is an efficient configuration employed widely for the solar membrane distillation desalination process. In the present work, 1-D Knudsen and molecular transport ...(KMT) model has been developed to investigate the performance of the flat sheet PVDF membrane. A new solution algorithm for the co-current and counter-current flow regime has been designed to solve the heat and mass transfer equations iteratively for a single-stage AGMD module. The feed temperature, feed flow rate, airgap size, salinity, membrane porosity and module length were varied and compared with experimental results. The increase in feed temperature from 40 °C to 80 °C resulted in 10.38 times increase in flux for co-current flow and 11.05 times for counter-current flow. The maximum permeate flux at 80 °C was 8.668 kg/m2h and 8.871 kg/m2h for the co-current and counter-current processes, respectively. Optimizing the feed temperature, flow rate, and membrane length using RSM suggests 80 °C, 1.528 LPM and 10 m as the optimum operating condition. An AGMD module of size 0.8 m width and 10 m length under the optimum operating condition exhibited a freshwater yield of 8.73 kg/h by consuming 24.98 kWh/m3 of specific energy, and the water production cost would be around $2.25/m3.
•A 1-D theoretical model is developed for AGMD and solved iteratively•The model is validated using the results obtained from the lab scale experimental setup•The feed water temperature, flow rate and membrane length are the key parameters that affects its performance•RSM is used for the optimization of the process to minimize the water production cost
P53 is critically important in preventing oncogenesis but its role in inflammation in general and in the function of inflammatory macrophages in particular is not clear. Here, we show that bone ...marrow-derived macrophages exhibit endogenous p53 activity, which is increased when macrophages are polarized to the M2 (alternatively activated macrophage) subtype. This leads to reduced expression of M2 genes. Nutlin-3a, which destabilizes the p53/MDM2 (mouse double minute 2 homolog) complex, promotes p53 activation and further downregulates M2 gene expression. In contrast, increased expression of M2 genes was apparent in M2-polarized macrophages from p53-deficient and p53 mutant mice. Furthermore, we show, in mice, that p53 also regulates M2 polarization in peritoneal macrophages from interleukin-4-challenged animals and that nutlin-3a retards the development of tolerance to Escherichia coli lipopolysaccharide. P53 acts via transcriptional repression of expression of c-Myc (v-myc avian myelocytomatosis viral oncogene homolog) gene by directly associating with its promoter. These data establish a role for the p53/MDM2/c-MYC axis as a physiological 'brake' to the M2 polarization process. This work reveals a hitherto unknown role for p53 in macrophages, provides further insight into the complexities of macrophage plasticity and raises the possibility that p53-activating drugs, many of which are currently being trialled clinically, may have unforeseen effects on macrophage function.
Tyrosine kinase inhibitors (TKIs) elicit high response rates among individuals with kinase-driven malignancies, including chronic myeloid leukemia (CML) and epidermal growth factor receptor-mutated ...non-small-cell lung cancer (EGFR NSCLC). However, the extent and duration of these responses are heterogeneous, suggesting the existence of genetic modifiers affecting an individual's response to TKIs. Using paired-end DNA sequencing, we discovered a common intronic deletion polymorphism in the gene encoding BCL2-like 11 (BIM). BIM is a pro-apoptotic member of the B-cell CLL/lymphoma 2 (BCL2) family of proteins, and its upregulation is required for TKIs to induce apoptosis in kinase-driven cancers. The polymorphism switched BIM splicing from exon 4 to exon 3, which resulted in expression of BIM isoforms lacking the pro-apoptotic BCL2-homology domain 3 (BH3). The polymorphism was sufficient to confer intrinsic TKI resistance in CML and EGFR NSCLC cell lines, but this resistance could be overcome with BH3-mimetic drugs. Notably, individuals with CML and EGFR NSCLC harboring the polymorphism experienced significantly inferior responses to TKIs than did individuals without the polymorphism (P = 0.02 for CML and P = 0.027 for EGFR NSCLC). Our results offer an explanation for the heterogeneity of TKI responses across individuals and suggest the possibility of personalizing therapy with BH3 mimetics to overcome BIM-polymorphism-associated TKI resistance.
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