Glioblastomas represent the most aggressive glioma grade and are associated with a poor patient prognosis. The current standard of care, consisting of surgery, radiation and chemotherapy, only ...results in a median survival of 14 months, underscoring the importance of developing effective new therapeutic strategies. Among the challenges in treating glioblastomas are primary resistance and the rapid emergence of recurrent disease, which can result from tumor cell-intrinsic mechanisms in addition to tumor microenvironment (TME)-mediated extrinsic resistance. Using a PDGF-B-driven proneural glioma mouse model, we assessed a panel of tyrosine kinase inhibitors with different selectivity profiles. We found that PLX3397, an inhibitor of colony stimulating factor-1 receptor (CSF-1R), blocks glioma progression, markedly suppresses tumor cell proliferation and reduces tumor grade. By contrast, the multi-targeted tyrosine kinase inhibitors dovitinib and vatalanib, which directly target tumor cells, exert minimal anti-tumoral effects in vivo, despite killing glioma cells in vitro, suggesting a TME-mediated resistance mechanism may be involved. Interestingly, PLX3397 interferes with tumor-mediated education of macrophages and consequently restores the sensitivity of glioma cells to tyrosine kinase inhibitors in vivo in preclinical combination trials. Our findings thus demonstrate that microenvironmental alteration by CSF-1R blockade renders tumor cells more susceptible to receptor tyrosine kinase inhibition in a preclinical glioblastoma model, which may have important translational relevance.
The optical response of semiconducting monolayer transition-metal dichalcogenides (TMDCs) is dominated by strongly bound excitons that are stable even at room temperature. However, substrate-related ...effects such as screening and disorder in currently available specimens mask many anticipated physical phenomena and limit device applications of TMDCs. Here, we demonstrate that that these undesirable effects are strongly suppressed in suspended devices. Extremely robust (photogain > 1,000) and fast (response time < 1 ms) photoresponse allow us to study, for the first time, the formation, binding energies, and dissociation mechanisms of excitons in TMDCs through photocurrent spectroscopy. By analyzing the spectral positions of peaks in the photocurrent and by comparing them with first-principles calculations, we obtain binding energies, band gaps and spin-orbit splitting in monolayer TMDCs. For monolayer MoS2, in particular, we obtain an extremely large binding energy for band-edge excitons, E bind ≥ 570 meV. Along with band-edge excitons, we observe excitons associated with a van Hove singularity of rather unique nature. The analysis of the source-drain voltage dependence of photocurrent spectra reveals exciton dissociation and photoconversion mechanisms in TMDCs.
Conceived to address challenges in modeling human biology, organ-on-a-chip (OOAC) engineering has grown enormously from tissue engineering to capture specific hallmarks of human tissues.The evolution ...of OOAC models is intertwined with progress in tissue engineering by applying cellular components, biomaterials, and tissue culture technologies.The manufacture of OOAC devices incorporates microfabrication techniques, material chemistry, and biosensing applications.Current OOAC platforms focus on constructing higher-order structures using tissue engineering principles. For example, liver- and heart-on-chips are used to study drug metabolism, toxicity, and pathology.Limitations in the OOAC field include achieving systematic biomimicry and stability. Synergistic incorporation of advanced cell culture and manufacturing techniques can expand the impact of OOAC platforms.
We review the emergence of the new field of organ-on-a-chip (OOAC) engineering, from the parent fields of tissue engineering and microfluidics. We place into perspective the tools and capabilities brought into the OOAC field by early tissue engineers and microfluidics experts. Liver-on-a-chip and heart-on-a-chip are used as two case studies of systems that heavily relied on tissue engineering techniques and that were amongst the first OOAC models to be implemented, motivated by the need to better assess toxicity to human tissues in preclinical drug development. We review current challenges in OOAC that often stem from the same challenges in the parent fields, such as stable vascularization and drug absorption.
Artemisia ordosica is one of the main shrubby perennials belonging to Artemisia species of Asteraceae and could be used in folk Chinese/Mongolian medicine to treat symptoms of various inflammatory ...ailments. The present study was conducted to investigate the protective effects of dietary Artemisia ordosica polysaccharide (AOP) against lipopolysaccharide (LPS) induced oxidative stress in broilers via Nrf2/Keap1 and TLR4/NF-κB pathway. A total of 192 1-day-old Arbor Acres male broilers were randomly allotted to four treatments with 6 replicates (n = 8): (1) CON group, non-challenged broilers fed basal diet; (2) LPS group, LPS-challenged broilers fed basal diet; (3) AOP group, non-challenged broilers fed basal diet supplemented with 750 mg/kg AOP; (4) LPS+AOP group, LPS-challenged broilers fed basal diet supplemented with 750 mg/kg AOP. The trial included starter phase (d 1–14), stress period Ⅰ (d 15–21), convalescence Ⅰ (d 22–28), stress period Ⅱ (d 29–35) and convalescence Ⅱ (d 36–42). During stress period Ⅰ (on d 15, 17, 19 and 21) and stress period Ⅱ (on d 29, 31, 33 and 35), broilers were injected intra-abdominally either with LPS solution or with an equal amount of sterile saline. The results showed that dietary AOP supplementation alleviated LPS-induced reduction in antioxidant enzyme activity and excessive production of ROS, 8-OHdG and PC in serum of broilers challenged with LPS. Moreover, dietary AOP supplementation alleviated the decrease of T-AOC and activities of SOD, CAT and GPx in liver of broilers challenged with LPS by increasing expression of Nrf2, and inhibiting over-expression of Keap1 both at gene and protein level. Additionally, dietary AOP supplementation decreased the over-production of IL-1β and IL-6 in liver of broilers challenged by LPS through decreasing mRNA expression of TLR4, MyD88, NF-κB P65, IL-1β and IL-6, and alleviating the increase of protein expression of TLR4, IKKβ, NF-κB P65, IL-1β, IL-6, and the decrease of protein expression of IkBα. In conclusion, dietary AOP supplementation could alleviate LPS-induced oxidative stress through Nrf2/Keap1 and TLR4/NF-κB pathway.
•Dietary AOP alleviated LPS-induced liver injure.•Dietary AOP relieved LPS-induced oxidative stress by activating Nrf2/keap1 pathway.•Dietary AOP relieved LPS-induced oxidative stress by suppressing TLR4/NF-κB pathway.
Background The consistent finding of a genetic susceptibility to prostate cancer suggests that there are germline sequence variants predisposing individuals to this disease. These variants could be ...useful in screening and treatment. Methods We performed an exploratory genome-wide association scan in 498 men with aggressive prostate cancer and 494 control subjects selected from a population-based case–control study in Sweden. We combined the results of this scan with those for aggressive prostate cancer from the publicly available Cancer Genetic Markers of Susceptibility (CGEMS) Study. Single-nucleotide polymorphisms (SNPs) that showed statistically significant associations with the risk of aggressive prostate cancer based on two-sided allele tests were tested for their association with aggressive prostate cancer in two independent study populations composed of individuals of European or African American descent using one-sided tests and the genetic model (dominant or additive) associated with the lowest value in the exploratory study. Results Among the approximately 60000 SNPs that were common to our study and CGEMS, we identified seven that had a similar (positive or negative) and statistically significant (P<.01) association with the risk of aggressive prostate cancer in both studies. Analysis of the distribution of these SNPs among 1032 prostate cancer patients and 571 control subjects of European descent indicated that one, rs1571801, located in the DAB2IP gene, which encodes a novel Ras GTPase-activating protein and putative prostate tumor suppressor, was associated with aggressive prostate cancer (one-sided P value = .004). The association was also statistically significant in an African American study population that included 210 prostate cancer patients and 346 control subjects (one-sided P value = .02). Conclusion A genetic variant in DAB2IP may be associated with the risk of aggressive prostate cancer and should be evaluated further.
Let
A
be a sequence of positive integers and
P(A)
be the set of all integers which are the finite sum of distinct terms of
A
. Let
B
=
{
b
1
<
b
2
<
⋯
}
be a sequence of positive integers with
b
1
∈
...{
4
,
7
,
8
}
∪
11
,
+
∞
)
. By observing the results of Chen and Fang 2, Fang and Fang 4 found that
3
b
1
+
5
is the critical value for
b
2
such that there exists a sequence
A
of positive integers for which
P
(
A
)
=
N
\
B
. For
b
2
=
3
b
1
+
5
, they considered the inverse problem and determined the critical value for
b
3
. Also, for
b
2
≥
3
b
1
+
5
, they asked for the critical value for
b
3
. In this paper, we solve this problem.
Summary
Breeding for good meat quality performance while maintaining large body size and desirable carcass traits has been the major challenge for modern swine selective breeding. To address this ...goal, in the present work we studied five related populations produced by two commercial breeds (Berkshire and Duroc) and two Chinese breeds (Licha black pig and Lulai black pig). A single‐trait GWAS performed on 20 body size and carcass traits using a self‐developed China Chip‐1 porcine SNP50K BeadChip identified 11 genome‐wide significant QTL on nine chromosomes and 22 suggestive QTL on 15 chromosomes. For the 11 genome‐wide significant QTL, eight were detected in at least two populations, and the rest were population‐specific and only mapped in Shanxia black pig. Most of the genome‐wide significant QTL were pleiotropic; for example, the QTL around 75.65 Mb on SSC4 was associated with four traits at genome‐wide significance level. After screening the genes within 50 kb of the top SNP for each genome‐wide significant QTL, NR6A1 and VRTN were chosen as candidate genes for vertebrae number; PLAG1 and BMP2 were identified as candidate genes for body size; and MC4R was the strong candidate gene for body weight. The four genes have been reported as candidates for thoracic vertebrae number, lumbar vertebrae number, carcass length and body weight respectively in previous studies. The effects of VRTN on thoracic vertebrae number, carcass length and body length have been verified in Shanxia black pig. Therefore, the VRTN genotype could be used in gene‐assisted selection, and this could accelerate genetic improvement of body size and carcass traits in Shanxia black pig.
An important aspect of energy dissipation in weakly collisional plasmas is that of energy partitioning between different species (e.g., protons and electrons) and between different energy channels. ...Here we analyse pressure–strain interaction to quantify the fractions of isotropic compressive, gyrotropic, and nongyrotropic heating for each species. An analysis of kinetic turbulence simulations is compared and contrasted with corresponding observational results from Magnetospheric Multiscale Mission data in the magnetosheath. In assessing how protons and electrons respond to different ingredients of the pressure–strain interaction, we find that compressive heating is stronger than incompressive heating in the magnetosheath for both electrons and protons, while incompressive heating is stronger in kinetic plasma turbulence simulations. Concerning incompressive heating, the gyrotropic contribution for electrons is dominant over the nongyrotropic contribution, while for protons nongyrotropic heating is enhanced in both simulations and observations. Variations with plasma β are also discussed, and protons tend to gain more heating with increasing β.
Oxygen isotope speleothem records exhibit coherent variability over the pan-Asian summer monsoon (AM) region. The hydroclimatic representation of these oxygen isotope records for the AM, however, has ...remained poorly understood. Here, combining an isotope-enabled Earth system model in transient experiments with proxy records, we show that the widespread AM δ
O
signal during the last deglaciation (20 to 11 thousand years ago) is accompanied by a continental-scale, coherent hydroclimate footprint, with spatially opposite signs in rainfall. This footprint is generated as a dynamically coherent response of the AM system primarily to meltwater forcing and secondarily to insolation forcing and is further reinforced by atmospheric teleconnection. Hence, widespread δ
O
depletion in the AM region is accompanied by a northward migration of the westerly jet and enhanced southwesterly monsoon wind, as well as increased rainfall from South Asia (India) to northern China but decreased rainfall in southeast China.
ABSTRACT
Using the short-cadence data (1-min interval) of the Kepler space telescope, we conducted a statistical analysis for the characteristic time of stellar flares on Sun-like stars (SLS). Akin ...to solar flares, stellar flares show rise and decay light-curve profiles, which reflect the two distinct phases (rise phase and decay phase) of the flare process. We derived characteristic times of the two phases for stellar flares of SLS, resulting in a median rise time of about 5.9 min and a median decay time of 22.6 min. It is found that both the rise time and the decay time of the stellar flares follow a lognormal distribution. The peak positions of the lognormal distributions for flare rise time and decay time are 3.5 min and 14.8 min, respectively. These time values for stellar flares are similar to the time-scale of solar flares, which supports the idea that stellar flares and solar flares have the same physical mechanism. The statistical results obtained in this work for SLS can be a benchmark of flare characteristic times when comparing with other types of stars.
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