The turbulent buoyant flows generated from a heat source block in a naturally ventilated cubical enclosure with vertical and horizontal openings are numerically investigated. Turbulence is modeled ...with large eddy simulation (LES) and the filtered governing equations are solved using an in-house code based on finite difference method (FDM). The time dependent flow characteristics are analyzed by varying the heat source aspect ratio (ϕ) in the range 0.25 ≤ϕ≤ 4.0 and the Grashof numbers (Gr) are varied between 107≤ Gr ≤ 1011. A chaotic flow behavior is observed inside the enclosure and the bidirectional exchange across the openings increases linearly with Grashof number. The results indicate that the heat source aspect ratio significantly impacts the thermal buoyancy force with the formation of multi-recirculating vortex cells inside the enclosure. A significant enhancement in the heat transfer rate and mass flow rates are observed after increasing the heat source aspect ratio. The results also indicate that the flow instabilities that develop across the vertical opening exceeded those across the horizontal opening. The present numerical results are in good agreement with the benchmark results reported in literature.
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•Heat source aspect ratio significantly affects thermal mixing.•Chaotic flow behavior with increase in Grashof number.•Formation of multi recirculating convective cells at higher Grashof number.•Heat transfer rate increases with increase in heat source aspect ratio.•Oscillatory flow behavior across openings increases with heat source aspect ratio.
PIK3CA, the gene for the lipid kinase p110α is one of the most frequently mutated oncogenes across all types of cancer. p110α is an enzyme that catalyzes the formation of phosphatidylinositol 3, 4, 5 ...Triphosphate (PIP3). PIP3 recruits effector proteins which regulate growth, proliferation and motility. Due to this role as a master cell regulator, the activity of p110α is maintained in an inactive confirmation and is only activated downstream of Receptor Tyrosine Kinases (RTKs) and RAS family of GTPases. p110α is maintained in an inactive confirmation through interactions with its regulatory subunit as well as inhibitory contacts with the C‐terminus. However, oncogenic mutations in p110α breaks these inhibitory interactions and drives hyperactivity without the need for activation signals leading to uncontrolled cell growth. We provide molecular insights into the regulation of oncogenic mutants of p110α using Hydrogen‐Deuterium Exchange Mass Spectrometry (HDX‐MS). HDX‐MS reveals the dynamic changes between the natural cytosolic state and fully‐active membrane bound states of the enzyme. We find unique molecular mechanisms regulating how mutants at the c‐terminus activate lipid kinase activity (H1047R, M1043L, G1049R and N1068KLKR). Using extensive biophysical tools, biochemical assays, and MD simulations, we have tested the oncogenic potential of these mutations. Our results elucidates a unifying theory towards the regulation of PI3Kα and how oncogenic mutations drive hyperactivity. This will aid in understanding the regulation of PI3Kα and in developing isoform specific inhibitors.
Environmental factors, including substance abuse and stress, cause long-lasting changes in the regulation of gene expression in the brain via epigenetic mechanisms, such as DNA methylation. We ...examined genome-wide DNA methylation patterns in the prefrontal cortex (PFC, BA10) of 25 pairs of control and individuals with alcohol use disorder (AUD), using the Infinium
MethylationEPIC BeadChip. We identified 5254 differentially methylated CpGs (p
< 0.005). Bioinformatic analyses highlighted biological processes containing genes related to stress adaptation, including the glucocorticoid receptor (encoded by NR3C1). Considering that alcohol is a stressor, we focused our attention on differentially methylated regions of the NR3C1 gene and validated the differential methylation of several genes in the NR3C1 network. Chronic alcohol drinking results in a significant increased methylation of the NR3C1 exon variant 1
, with a particular increase in the levels of 5-hydroxymethylcytosine over 5-methylcytosine. These changes in DNA methylation were associated with reduced NR3C1 mRNA and protein expression levels in PFC, as well as other cortico-limbic regions of AUD subjects when compared with controls. Furthermore, we show that the expression of several stress-responsive genes (e.g., CRF, POMC, and FKBP5) is altered in the PFC of AUD subjects. These stress-response genes were also changed in the hippocampus, a region that is highly susceptible to stress. These data suggest that alcohol-dependent aberrant DNA methylation of NR3C1 and consequent changes in other stress-related genes might be fundamental in the pathophysiology of AUD and lay the groundwork for treatments targeting the epigenetic mechanisms regulating NR3C1 in AUD.
Methotrexate for treating rheumatoid arthritis Lopez‐Olivo, Maria Angeles; Siddhanamatha, Harish R; Shea, Beverley ...
Cochrane database of systematic reviews,
06/2014, Letnik:
2014, Številka:
6
Journal Article
Recenzirano
Odprti dostop
Background
Methotrexate is a folic acid antagonist widely used for the treatment of neoplastic disorders. Methotrexate inhibits the synthesis of deoxyribonucleic acid (DNA), ribonucleic acid (RNA) ...and proteins by binding to dihydrofolate reductase. Currently, methotrexate is among the most commonly used drugs for the treatment of rheumatoid arthritis (RA). This is an update of the previous Cochrane systematic review published in 1997.
Objectives
To evaluate short term benefits and harms of methotrexate for treating RA compared to placebo.
Search methods
The Cochrane Musculoskeletal Group Trials Register, The Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE were searched from 1966 to 1997 and then updated to November 2013. The search was complemented with a bibliography search of the reference lists of trials retrieved from the electronic search.
Selection criteria
Randomized controlled trials and controlled clinical trials comparing methotrexate (MTX) monotherapy against placebo alone in people with RA. Any trial duration and MTX doses were included.
Data collection and analysis
Two review authors independently determined which studies were eligible for inclusion, extracted data and assessed risk of bias. Outcomes were pooled using mean differences (MDs) for continuous variables or standardized mean differences (SMDs) when different scales were used to measure the same outcome. Pooled risk ratio (RR) was used for dichotomous variables. Fixed‐effect models were used throughout, although random‐effects models were used for outcomes showing heterogeneity.
Main results
Five trials with 300 patients were included in the original version of the review. An additional two trials with 432 patients were added to the 2013 update of the review for a total of 732 participants. The trials were generally of unclear to low risk of bias with a follow‐up duration ranging from 12 to 52 weeks. All trials included patients who have failed prior treatment (for example, gold therapy, D‐penicillamine, azathioprine or anti‐malarials); mean disease duration that ranged between 1 and 14 years with six trials reporting more than 4 years; and weekly doses that ranged between 5 mg and 25 mg.
Benefits
Statistically significant and clinically important differences were observed for most efficacy outcomes. MTX monotherapy showed a clinically important and statistically significant improvement in the American College of Rheumatology (ACR) 50 response rate when compared with placebo at 52 weeks (RR 3.0, 95% confidence interval (CI) 1.5 to 6.0; number needed to treat (NNT) 7, 95% CI 4 to 22). Fifteen more patients out of 100 had a major improvement in the ACR 50 outcome compared to placebo (absolute treatment benefit (ATB) 15%, 95% CI 8% to 23%).
Statistically significant improvement in physical function (scale of 0 to 3) was also observed in patients receiving MTX alone compared with placebo at 12 to 52 weeks (MD ‐0.27, 95% CI ‐0.39 to ‐0.16; odds ratio (OR) 2.8, 95% CI 0.23 to 32.2; NNT 4, 95% CI 3 to 7). Nine more patients out of 100 improved in physical function compared to placebo (ATB ‐9%, 95% CI ‐13% to ‐5.3%). Similarly, the proportion of patients who improved at least 20% on the Short Form‐36 (SF‐36) physical component was higher in the MTX‐treated group compared with placebo at 52 weeks (RR 1.5, 95% CI 1.0 to 2.1; NNT 9, 95% CI 4 to 539). Twelve more patients out of 100 showed an improvement of at least 20% in the physical component of the quality of life measure compared to placebo (ATB 12%, 95% CI 1% to 24%). No clinically important or statistically significant differences were observed in the SF‐36 mental component.
Although no statistically significant differences were observed in radiographic scores (that is, Total Sharp score, erosion score, joint space narrowing), radiographic progression rates (measured by an increase in erosion scores of more than 3 units on a scale ranging from 0 to 448) were statistically significantly lower for patients in the MTX group compared with placebo‐treated patients (RR 0.31, 95% CI 0.11 to 0.86; NNT 13, 95% CI 10 to 60). Eight more patients out of 100 showed less damage to joints measured by an increase in erosion scores compared to placebo (ATB ‐8%, 95% CI ‐16% to ‐1%). In the one study measuring remission, no participants in either group met the remission criteria. These are defined by at least five of (≥ 2 months): morning stiffness of < 15 minutes, no fatigue, no joint pain by history, no joint tenderness, no joint swelling, and Westergren erythrocyte sedimentation rate (ESR) of < 20 mm/hr in men and < 30 mm/hr in women.
Harms
Patients in the MTX monotherapy group were twice as likely to discontinue from the study due to adverse events compared to patients in the placebo group, at 12 to 52 weeks (16% versus 8%; RR 2.1, 95% CI 1.3 to 3.3; NNT 13, 95% CI 6 to 44). Compared to placebo, nine more people out of 100 who took MTX withdrew from the studies because of side effects (ATB 9%, 95% CI 3% to 14%). Total adverse event rates at 12 weeks were higher in the MTX monotherapy group compared to the placebo group (45% versus 15%; RR 3.0, 95% CI 1.4 to 6.4; NNT 4, 95% CI 2 to 17). Thirty more people out of 100 who took MTX compared to those who took placebo experienced any type of side effect (common or rare) (ATB 30, 95% CI 13% to 47%). No statistically significant differences were observed in the total number of serious adverse events between the MTX group and the placebo group at 27 to 52 weeks. Three people out of 100 who took MTX alone experienced rare but serious side effects compared to 2 people out of 100 who took a placebo (3% versus 2%, respectively).
Authors' conclusions
Based on mainly moderate to high quality evidence, methotrexate (weekly doses ranging between 5 mg and 25 mg) showed a substantial clinical and statistically significant benefit compared to placebo in the short term treatment (12 to 52 weeks) of people with RA, although its use was associated with a 16% discontinuation rate due to adverse events.
Beetroot is rich in various bioactive phytochemicals, which are beneficial for human health and exert protective effects against several disease conditions like cancer, atherosclerosis, etc. Beetroot ...has various therapeutic applications, including antioxidant, antibacterial, antiviral, and analgesic functions. Besides the pharmacological effects, food industries are trying to preserve beetroots or their phytochemicals using various food preservation methods, including drying and freezing, to preserve their antioxidant capacity. Beetroot is a functional food due to valuable active components such as minerals, amino acids, phenolic acid, flavonoid, betaxanthin, and betacyanin. Due to its stability, nontoxic and non-carcinogenic and nonpoisonous capabilities, beetroot has been used as an additive or preservative in food processing. Beetroot and its bioactive compounds are well reported to possess antioxidant, anti-inflammatory, antiapoptotic, antimicrobial, antiviral, etc. In this review, we provided updated details on (i) food processing, preservation and colorant methods using beetroot and its phytochemicals, (ii) synthesis and development of several nanoparticles using beetroot and its bioactive compounds against various diseases, (iii) the role of beetroot and its phytochemicals under disease conditions with molecular mechanisms. We have also discussed the role of other phytochemicals in beetroot and their health benefits. Recent technologies in food processing are also updated. We also addressed on molecular docking-assisted biological activity and screening for bioactive chemicals. Additionally, the role of betalain from different sources and its therapeutic effects have been listed. To the best of our knowledge, little or no work has been carried out on the impact of beetroot and its nanoformulation strategies for phytocompounds on antimicrobial, antiviral effects, etc. Moreover, epigenetic alterations caused by phytocompounds of beetroot under several diseases were not reported much. Thus, extensive research must be carried out to understand the molecular effects of beetroot in the near future.
•Smoke removal in tunnel fire is significant with multiple ceiling vents.•Significant change in tunnel flow characteristics by varying heat source and ceiling vent locations.•As distance from fire ...source and ceiling vent increases smoke venting efficiency decreases.•Tunnel temperature distribution increases with decrease in vent size.
The present article highlights the performance of natural roof ventilation systems and its effects on tunnel fire flow characteristics. Numerical analysis is performed using Large Eddy Simulations (LES) to predict fire growth rate and smoke movement in tunnel with single and multiple roof openings. The smoke venting performance of ceiling vents are investigated by varying the vent size and fire source locations. The critical parameters such as mass flow rate through ceiling openings, smoke traveling time and fire growth patterns are presented. The ceiling openings are effective in transferring hot gases and reduces the longitudinal smoke velocity. The heat source and ceiling vent locations significantly affects the vent performance and smoke behavior in tunnel. The present results are in good agreement with the experimental results available in literature.
Theobroma cacao L. is a commercially important food/beverage and is used as traditional medicine worldwide against a variety of ailments. In the present study, computational biology approaches were ...implemented to elucidate the possible role of cocoa in cancer therapy. Bioactives of cocoa were retrieved from the PubChem database and queried for targets involved in cancer pathogenesis using BindingDB (similarity index ≥0.7). Later, the protein-protein interactions network was investigated using STRING and compound-protein via Cytoscape. In addition, intermolecular interactions were investigated via molecular docking. Also, the stability of the representative complex Hirsutrin-epidermal growth factor receptor (EGFR) complex was explored using molecular dynamics simulations. Crude extract metabolite profile was carried out by LC-MS. Further, anti-oxidant and cytotoxicity studies were performed in Chinese hamster ovary (normal) and Ehrlich ascites carcinoma (cancer) cell lines. Herein, the gene set enrichment and network analysis revealed 34 bioactives in cocoa targeting 50 proteins regulating 21 pathways involved in cancer and oxidative stress in humans. EGFR scored the highest edge count amongst 50 targets modulating 21 key pathways. Hence, it was selected as a promising anticancer target in this study. Structural refinement of EGFR was performed via all-atom molecular dynamics simulations in explicit solvent. A complex EGFR-Hirsutrin showed the least binding energy (-7.2 kcal/mol) and conserved non-bonded contacts with binding pocket residues. A stable complex formation of EGFR-Hirsutrin was observed during 100 ns MD simulation. In vitro studies corroborated antioxidant activity for cocoa extract and showed a significantly higher cytotoxic effect on cancer cells compared to normal cells. Our study virtually predicts anti-cancer activity for cocoa affected by hirsutrin inhibiting EGFR. Further wet-lab studies are needed to establish cocoa extract against cancer and oxidative stress.
In this study a few galaxies are considered as samples from the atlas of spiral galaxies for estimating the acceleration constant
a
0
of Modified Newtonian dynamics (MOND). Considering the model of ...flat disk galaxy, the values of disk acceleration due to gravity (
g
disk
)
are obtained which is equivalent to Newtonian gravity (
g
N
). This is further helpful in determining
a
0
through modified Newtonian dynamics. The values obtained are 0.069–1.78 (
×
10
-
13
km
/
s
2
)
. Out of which 0.7–1.33 (
×
10
-
13
km
/
s
2
)
are in a good agreement with the observed values. The MOND induced rotation curves of the galaxies are studied for the following interpolating functions:
μ
x
=
x
(
1
+
x
2
)
-
1
2
,
μ
x
=
x
1
+
x
and
μ
x
=
1
-
e
-
x
. This modification yields flat rotation curves. These curves are analyzed and compared with observational data. The simple interpolating function
μ
x
=
x
1
+
x
is found to be a better fit to MOND. Also, the relation between acceleration constant and the surface mass density have been obtained and it is observed that acceleration constant increases with increase of surface mass density.
Positive effects of alcohol drinking such as anxiolysis and euphoria appear to be a crucial factor in the initiation and maintenance of alcohol use disorder (AUD). However, the mechanisms that lead ...from chromatin reorganization to transcriptomic changes after acute ethanol exposure remain unknown. Here, we used Assay for Transposase-Accessible Chromatin followed by high throughput sequencing (ATAC-seq) and RNA-seq to investigate epigenomic and transcriptomic changes that underlie anxiolytic effects of acute ethanol using an animal model. Analysis of ATAC-seq data revealed an overall open or permissive chromatin state that was associated with transcriptomic changes in the amygdala after acute ethanol exposure. We identified a candidate gene, Hif3a (Hypoxia-inducible factor 3, alpha subunit), that had 'open' chromatin regions (ATAC-seq peaks), associated with significantly increased active epigenetic histone acetylation marks and decreased DNA methylation at these regions. The mRNA levels of Hif3a were increased by acute ethanol exposure, but decreased in the amygdala during withdrawal after chronic ethanol exposure. Knockdown of Hif3a expression in the central nucleus of amygdala attenuated acute ethanol-induced increases in Hif3a mRNA levels and blocked anxiolysis in rats. These data indicate that chromatin accessibility and transcriptomic signatures in the amygdala after acute ethanol exposure underlie anxiolysis and possibly prime the chromatin for the development of AUD.
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