p53 Impact Reactive Oxygen Species and Drug Resistance in Multiple Myeloma

Multiple myeloma (MM) is an incurable blood cancer characterized by the proliferation of malignant plasma cells. Several recurrent genetic alterations occur in MM, but mutations in the TP53 gene are associated with the worst clinical outcomes due to the rapid development of drug-resistant disease. The p53 protein, coded by the TP53 gene, is a tumor suppressor involved in coordinating responses to cellular stress, such as DNA damage, that lead to cell cycle arrest and apoptosis. Most chemotherapies lead to increased intracellular reactive oxygen species (ROS) levels, and ROS can activate p53, signal downstream of TP53, and be regulated by TP53 target genes. In MM, it is not clear whether p53 mutations impact ROS levels and whether changes in ROS are associated with drug resistance. We examined the impact of the loss of p53 via knockout of TP53 (p53KO) on ROS levels and drug sensitivity in the MM1.S myeloma cell line. We also found that baseline ROS levels were significantly lower in p53KO cells than in control cells from each MM cell line (p<0.05). Compared to wild-type cells, we also found that the IC50 of doxorubicin was approximately two-fold higher in p53KO cells (p<0.05). When cells were treated with N-acetyl cysteine (NAC), a ROS scavenger, and doxorubicin for 24 hours, ROS levels were significantly lowered compared to the doxorubicin single control cells in both control and p53KO cells (p<0.05). Furthermore, treatment with NAC significantly enhanced doxorubicin resistance (p<0.05). Our findings suggest that lower ROS levels are a characteristic of p53 loss, both before and after doxorubicin treatment, and the attenuation of ROS in p53KO cells leads to drug resistance. Overall, these studies will lead to a better understanding of the relationship between p53, ROS levels, and drug resistance and may lead to new strategies to improve the efficacy of chemotherapy in mutant p53 MM.Biochemistr

Incipient ferralization and weathering indices along a soil chronosequence in Taiwan

The low hilly topography of Green Island, a volcanic island off southeastern Taiwan, includes an altitudinal sequence of sub-horizontal benches. We examined eight profiles along this sequence, ranging from pale brown loamy coral sand on the lowest bench that fringes the coast at an elevation of about 10 m to deep, intensely red and acid clay on the highest bench at about 240 m. Chemical analyses, differential Fe extractions, thin sections, X-ray diffraction of the clay minerals and indices of pedochemical weathering and strain indicated that soil development progressed by weathering of primary and secondary phyllosilicates through argilluviation in the intermediate stages to the generation of increasing quantities of free Fe. The Fe accumulates as free sesquioxides, which crystallize with age. Taxonomically the soil types progress from sandy coral Arenosol, through Eutric Cambisol, Hypereutric Lixisol and Acrisol to incipient Ferralsol (Udipsamment → Eutrudept → Udalf → Udultisol → Udox in Soil Taxonomy). The profiles are interpreted as a chronosequence, although this is complicated by minor and upwardly diminishing contributions of reef coral to the mainly igneous parent materials. There are also variations in the andesitic-basaltic bedrock, and minor aeolian inputs in the higher and older soil types. Regional eustatic sea-level correlations, 14C dating of carbonates on the two lowest benches and estimates of local tectonic uplift indicate that the incipient Ferralsols on the upper bench might date from about 150 ka. The transition through argilluvial Acrisols to incipient sesquioxide-dominated Ferralsols appears, therefore, to develop within 100–200 ka on Green Island, which is faster than usual

3D fatigue from stereoscopic 3D video displays: Comparing objective and subjective tests using electroencephalography

The use of stereoscopic display has increased in recent times, with a growing range of applications using 3D videos for visual entertainment, data visualization, and medical applications. However, stereoscopic 3D video can lead to adverse reactions amongst some viewers, including visual fatigue, headache and nausea; such reactions can further lead to Visually Induced Motion Sickness (VIMS). Whilst motion sickness symptoms can occur from other types of visual displays, this paper investigates the rapid adjustment triggered by human pupils as a potential cause of 3D fatigue due to VIMS from stereoscopic 3D displays. Using Electroencephalogram (EEG) biosignals and eye blink tools to measure the 3D fatigue, a series of objective and subjective experiments were conducted to investigate the effect of stereoscopic 3D across a series of video sequences

Impact of salt crystal size on in-mouth delivery of sodium and saltiness perception from snack foods

Fried, sliced potato crisps were flavored with sodium chloride of varying size fractions to investigate the impact of salt crystal size on the delivery rate of sodium to the tongue and resultant saltiness, measured over 65 s with a defined chew protocol (three chews, then holding the bolus in the mouth without swallowing). Salt crystal size impacted upon the delivery rate and perceived saltiness. The smallest crystal size fraction dissolved and diffused throughout the mouth to the tongue saliva faster than the medium and the largest ones; the smallest crystal size fraction also had the highest maximum concentration and greatest total sodium. These results correlated well with the sensory perceived saltiness, where the smallest crystal size fraction resulted in the fastest Tmax, highest maximum saltiness intensity and maximum total saltiness. The different delivery rates can be explained by differential dissolution kinetics and enhanced mass transfer of sodium across the saliva

Large collective Lamb shift of two distant superconducting artificial atoms

Virtual photons can mediate interaction between atoms, resulting in an energy shift known as a collective Lamb shift. Observing the collective Lamb shift is challenging, since it can be obscured by radiative decay and direct atom-atom interactions. Here, we place two superconducting qubits in a transmission line terminated by a mirror, which suppresses decay. We measure a collective Lamb shift reaching 0.8% of the qubit transition frequency and exceeding the transition linewidth. We also show that the qubits can interact via the transmission line even if one of them does not decay into it.Comment: 7+5 pages, 4+2 figure

Rap1 up-regulation and activation on plasma membrane regulates T cell adhesion

Rap1 and Ras are closely related GTPases that share some effectors but have distinct functions. We studied the subcellular localization of Rap1 and its sites of activation in living cells. Both GFP-tagged Rap1 and endogenous Rap1 were localized to the plasma membrane (PM) and endosomes. The PM association of GFP-Rap1 was dependent on GTP binding, and GFP-Rap1 was rapidly up-regulated on this compartment in response to mitogens, a process blocked by inhibitors of endosome recycling. A novel fluorescent probe for GTP-bound Rap1 revealed that this GTPase was transiently activated only on the PM of both fibroblasts and T cells. Activation on the PM was blocked by inhibitors of endosome recycling. Moreover, inhibition of endosome recycling blocked the ability of Rap1 to promote integrin-mediated adhesion of T cells. Thus, unlike Ras, the membrane localizations of Rap1 are dynamically regulated, and the PM is the principle platform from which Rap1 signaling emanates. These observations may explain some of the biological differences between these GTPases

Repeated Small Perturbation Approach Reveals Transcriptomic Steady States

The study of biological systems dynamics requires elucidation of the transitions of steady states. A “small perturbation” approach can provide important information on the “steady state” of a biological system. In our experiments, small perturbations were generated by applying a series of repeating small doses of ultraviolet radiation to a human keratinocyte cell line, HaCaT. The biological response was assessed by monitoring the gene expression profiles using cDNA microarrays. Repeated small doses (10 J/m2) of ultraviolet B (UVB) exposure modulated the expression profiles of two groups of genes in opposite directions. The genes that were up-regulated have functions mainly associated with anti-proliferation/anti-mitogenesis/apoptosis, and the genes that were down-regulated were mainly related to proliferation/mitogenesis/anti-apoptosis. For both groups of genes, repetition of the small doses of UVB caused an immediate response followed by relaxation between successive small perturbations. This cyclic pattern was suppressed when large doses (233 or 582.5 J/m2) of UVB were applied. Our method and results contribute to a foundation for computational systems biology, which implicitly uses the concept of steady state

Ligands in PSI structures

A survey of the types and frequency of ligands that are bound to PSI structures is analyzed as well as their utility in functional annotation of previously uncharacterized proteins

Peroxidase-like molybdenum oxides/nitrogen-doped graphene quantum dot as the smartphone-based immunosensing probe for the ultrasensitive detection of neurofilament light chain in human serum

Nanozyme possesses multiple advantages including low cost, high stability, easy manufacture, and versatility, which have earned interest in the application of biomedical purposes. Herein, the nitrogen-graphene quantum dot (N-GQDs) decorated mixed molybdenum oxides (MMO, MoOx, 2 < x < 3) were hydrothermally fabricated to serve as the peroxidase-like nanozymes for the ultrasensitive detection of neurofilament light chain (NfL). The kinetics parameters of nanozyme including maximum velocity (Vmax) and Michaelis-Menten half-saturation constant (Km) were examined and compared with natural horseradish peroxidase (HRP). In addition, the detection principle of MMO/N-GQD-based immunosensor was established. Results show that addition of N-GQDs can trigger the electron flow from N-GQDs to MMO, making the redox center of Mo elements more effective on electron transfer. The MMO/N-GQDs/PPL/anti-NfL immunosensor exhibits excellent analytical performance on NfL detection with both UV–visible spectrophotometer or smartphone-oriented RGB reader. A linear range of 16–1000 pg mL−1 with a limit of detection of 2.24 pg mL−1 and recovery of 83 – 104 % in human serum is achieved. The immunosensor can attain a selectivity coefficient of higher than 0.7 against interferences containing common ions, amino acids, cholesterol, and biomarkers in serum. Results corroborate that the green-synthesized peroxidase-like MMO/N-GQD possesses the advantages of cost-effective and high scalability, which can serve as a potential nanozyme to replace natural enzyme for the ultrasensitive and selective detection of serum NfL with superior recovery in human serum