Mounting evidence shows that selenium possesses chemotherapeutic potential against tumor cells, including leukemia, prostate cancer and colorectal cancer (CRC) cells. However, the detailed mechanism ...by which sodium selenite specifically kills tumor cells remains unclear. Herein, we demonstrated that supranutritional doses of selenite-induced apoptosis in CRC cells through reactive oxygen species (ROS)-dependent modulation of the PI3K/AKT/FoxO3a signaling pathway. First, we found that selenite treatment in HCT116 and SW480 CRC cells caused inhibition of AKT and the nuclear accumulation of FoxO3a by western blot and immunofluorescence analyses, respectively, thereby facilitating transcription of the target genes bim and PTEN. Modulation of the AKT/FoxO3a/Bim signaling pathway by chemical inhibitors or RNA interference revealed that these events were critical for selenite-induced apoptosis in CRC cells. Additionally, we discovered that FoxO3a-mediated upregulation of PTEN exerted a further inhibitory effect on the AKT survival pathway. We also corroborated our findings in vivo by performing immunohistochemistry experiments. In summary, our results show that selenite could induce ROS-dependent FoxO3a-mediated apoptosis in CRC cells and xenograft tumors through PTEN-mediated inhibition of the PI3K/AKT survival axis. These results help to elucidate the molecular mechanisms underlying selenite-induced cell death in tumor cells and provide a theoretical basis for translational applications of selenium.
Ketosis is one of the most prevalent and complex metabolic disorders in high-producing dairy cows and usually detected through analyses of β-hydroxybutyrate (BHB) concentration in blood. Our main ...objectives were to evaluate genetic parameters for blood BHB predicted based on Fourier-transform mid-infrared spectra from 5 to 305 d in milk, and estimate the genetic relationships of blood BHB with 7 reproduction traits and 6 longevity traits in Holstein cattle. Predicted blood BHB records of 11,609 Holstein cows (after quality control) were collected from 2016 to 2019 and used to derive 4 traits based on parity number, including predicted blood BHB in all parities (BHBp), parity 1 (BHB1), parity 2 (BHB2), and parity 3+ (BHB3). Single- and multitrait repeatability models were used for estimating genetic parameters for the 4 BHB traits. Random regression test-day models implemented via Bayesian inference were used to evaluate the daily genetic feature of BHB variability. In addition, genetic correlations were calculated for the 4 BHB traits with reproduction and longevity traits. The heritability estimates of BHBp, BHB1, BHB2, and BHB3 ranged from 0.100 ± 0.026 (± standard error) to 0.131 ± 0.023. The BHB in parities 1 to 3+ were highly genetically correlated and ranged from 0.788 (BHB1 and BHB2) to 0.911 (BHB1 and BHB3). The daily heritability of BHBp ranged from 0.069 to 0.195, higher for the early and lower for the later lactation periods. A similar trend was observed for BHB1, BHB2, and BHB3. There are low direct genetic correlations between BHBp and selected reproductive performance and longevity traits, which ranged from −0.168 ± 0.019 (BHBp and production life) to 0.157 ± 0.019 (BHBp and age at first calving) for the early lactation stage (5 to 65 d). These direct genetic correlations indicate that cows with higher BHBp (greater likelihood of having ketosis) in blood usually have shorter production life (−0.168 ± 0.019). Cows with higher fertility and postpartum recovery, such as younger age at first calving (0.157 ± 0.019) and shorter interval from calving to first insemination in heifer (0.111 ± 0.006), usually have lower BHB concentration in the blood. Furthermore, the direct genetic correlations change across parity and lactation stage. In general, our results suggest that selection for lower predicted BHB in early lactation could be an efficient strategy for reducing the incidence of ketosis as well as indirectly improving reproductive and longevity performance in Holstein cattle.
Tension cracks were generated by past megathrust earthquakes along the coastal forearc of Chile‐Peru. To explain why elastic rebound in an offshore earthquake can cause widespread permanent ...deformation onshore, we propose a model in which the near‐surface material exhibits viscoelastic behavior, analogous to laboratory‐observed behavior of petroleum reservoir rocks. Because of near‐surface relaxation, interseismic deformation builds up stress only in the deeper crust. Elastic rebound of the deeper crust during an earthquake induces near‐surface tension to generate cracks. We numerically demonstrate the proposed mechanism using hypothetical and real megathrust earthquakes. The location of the zone of peak tension, assumed to be responsible for the crack generation, is controlled by downdip rupture termination. A rupture farther downdip or terminating more gradually causes the zone of peak tension to be farther landward and broader. The tension cracks thus may contain important information on megathrust rupture dynamics.
Plain Language Summary
Earthquakes are the operation of elastic rebound. Tension cracks induced by megathrust earthquakes observed in Chile‐Peru therefore require special explanation. In this work, we propose a testable model for these cracks. We propose that the cemented soil and the highly fractured shallow bedrock in this area exhibit a viscoelastic behavior analogous to petroleum reservoir rocks. When the megathrust is locked in preparation for the next earthquake, the deeper crust is elastically shortened like a spring, but the shallow material deforms in a viscous fashion and do not store energy. During the megathrust earthquake, elastic rebound of the deeper crust induces tension in the shallow material, causing it to crack. If we assume that the observed crack distribution is controlled by the peak tension during the earthquake, it can be used to constrain how the megathrust rupture terminates in the deep end, which helps to understand the physics of earthquakes.
Key Points
Viscoelastic relaxation of near‐surface material allows permanent interseismic shortening contemporaneous with deeper elastic deformation
Elastic rebound of deeper crust in earthquakes induces tension in the relaxed shallow material, explaining cracks in Chile‐Peru forearc
Crack distribution, assumed to be controlled by peak coseismic tension, contains important information on megathrust rupture termination
Age-related eye diseases are becoming more prevalent. A notable increase has been seen in the most common causes including glaucoma, age-related macular degeneration (AMD), and cataract. Current ...clinical treatments vary from tissue replacement with polymers to topical eye drops and intravitreal injections. Research and development efforts have increased using polymers for sustained release to the eye to overcome treatment challenges, showing promise in improving drug release and delivery, patient experience, and treatment compliance. Polymers provide unique properties that allow for specific engineered devices to provide improved treatment options. Recent work has shown the utilization of synthetic and biopolymer derived biomaterials in various forms, with this review containing a focus on polymers Food and Drug Administration (FDA) approved for ocular use.
This provides an overview of some prevalent synthetic polymers and biopolymers used in ocular delivery and their benefits, brief discussion of the various types and synthesis methods used, and administration techniques. Polymers approved by the FDA for different applications in the eye are listed and compared to new polymers being explored in the literature. This article summarizes research findings using polymers for ocular drug delivery from various stages: laboratory, preclinical studies, clinical trials, and currently approved. This review also focuses on some of the challenges to bringing these new innovations to the clinic, including limited selection of approved polymers.
Polymers help improve drug delivery by increasing solubility, controlling pharmacokinetics, and extending release. Several polymer classes including synthetic, biopolymer, and combinations were discussed along with the benefits and challenges of each class. The ways both polymer synthesis and processing techniques can influence drug release in the eye were discussed.
The use of biomaterials, specifically polymers, is a well-studied field for drug delivery, and polymers have been used as implants in the eye for over 75 years. Promising new ocular drug delivery systems are emerging using polymers an innovative option for treating ocular diseases because of their tunable properties. This review touches on important considerations and challenges of using polymers for sustained ocular drug delivery with the goal translating research to the clinic.
The genomic DNA profiles of prostate cancers with aggressive features were compared to the profiles of matched normal DNA to identify genes that are selectively amplified in the cancer cells. One of ...the identified genes, MCM7, which is a component of the DNA replication licensing complex, has been studied extensively both at the DNA and protein levels in human prostate tissues. Approximately half of the prostate cancer specimens studied showed MCM7 gene amplification, and 60% of the aggressive prostate cancer specimens had increased MCM7 protein expression. Amplification or overexpression of MCM7 was significantly associated with relapse, local invasion and a worse tumor grade. Constitutive expression of MCM7 in a human prostate cancer cell line, DU145, resulted in markedly increased DNA synthesis and cell proliferation compared to vector-only controls, and an increased cell invasion in vitro. Indeed, MCM7 overexpression produced primary tumors 12 times larger than vector-only controls and resulted in a rapid demise of mice bearing those tumors. These studies implicate MCM7, and the DNA replication licensing gene family, in prostate cancer progression, growth and invasion.
Regulations play an important role in assuring the construction quality. However, due to the large amount of regulation needs considered, the construction quality compliance checking against ...regulations can be cumbersome/time-consuming and error prone. In order to give more computerized support to the construction quality compliance checking against regulations, an ontology-based semantic modeling approach of regulation constraints is explored. A meta model for construction quality inspection and evaluation i.e. CQIEOntology is proposed in this paper. Based on CQIEontology, the regulation constraints are modeled into OWL axioms and SWRL rules. By these OWL axioms and SWRL rules, the regulation provisions imposed on construction quality inspection can be translated into a set of inspection tasks, and get associated with the specific construction tasks. Once the construction starts, the applicable inspection tasks, including a series of quality checking and evaluation, will be reminded and recommended. Obviously, the proposed approach facilitates taking the construction quality compliance checking as a paralleling activity to the construction rather than an afterthought, and helps the inspectors in quality inspection. Finally, the approach is demonstrated in Protégé 3.4.6 through case studies based on regulation examples taken from “Code for Acceptance of Construction Quality of Building Foundation (GB50202-2002) and the validation and discussion are given for it.”
► A meta model for construction quality inspection and evaluation is proposed. ► Ontology and semantic technologies are selected to model the relevant knowledge. ► The approach is tested and assessed. ► Helping inspectors implement quality checking against relevant regulations.
The coronavirus disease 2019 (COVID-19) pandemic has resulted in millions of patients infected worldwide and indirectly affecting even more individuals through disruption of daily living. Long-term ...adverse outcomes have been reported with similar diseases from other coronaviruses, namely Middle East Respiratory Syndrome (MERS) and Severe Acute Respiratory Syndrome (SARS). Emerging evidence suggests that COVID-19 adversely affects different systems in the human body. This review summarizes the current evidence on the short-term adverse health outcomes and assesses the risk of potential long-term adverse outcomes of COVID-19. Major adverse outcomes were found to affect different body systems: immune system (including but not limited to Guillain-Barré syndrome and paediatric inflammatory multisystem syndrome), respiratory system (lung fibrosis and pulmonary thromboembolism), cardiovascular system (cardiomyopathy and coagulopathy), neurological system (sensory dysfunction and stroke), as well as cutaneous and gastrointestinal manifestations, impaired hepatic and renal function. Mental health in patients with COVID-19 was also found to be adversely affected. The burden of caring for COVID-19 survivors is likely to be huge. Therefore, it is important for policy makers to develop comprehensive strategies in providing resources and capacity in the healthcare system. Future epidemiological studies are needed to further investigate the long-term impact on COVID-19 survivors.
The purpose of this work is to gain knowledge on kinetics of biomass decomposition under oxidative atmospheres, mainly examining effect of heating rate on different biomass species. Two sets of ...experiments are carried out: the first set of experiments is thermal decomposition of four different wood particles, namely aspens, birch, oak and pine under an oxidative atmosphere and analysis with TGA; and the second set is to use large size samples of wood under different heat fluxes in a purpose-built furnace, where the temperature distribution, mass loss and ignition characteristics are recorded and analyzed by a data post-processing system. The experimental data is then used to develop a two-step reactions kinetic scheme with low and high temperature regions while the activation energy for the reactions of the species under different heating rates is calculated. It is found that the activation energy of the second stage reaction for the species with similar constituent fractions tends to converge to a similar value under the high heating rate.
Amino acid repeats (AARs) are abundant in protein sequences. They have particular roles in protein function and evolution. Simple repeat patterns generated by DNA slippage tend to introduce length ...variations and point mutations in repeat regions. Loss of normal and gain of abnormal function owing to their variable length are potential risks leading to diseases. Repeats with complex patterns mostly refer to the functional domain repeats, such as the well-known leucine-rich repeat and WD repeat, which are frequently involved in protein–protein interaction. They are mainly derived from internal gene duplication events and stabilized by ‘gate-keeper’ residues, which play crucial roles in preventing inter-domain aggregation. AARs are widely distributed in different proteomes across a variety of taxonomic ranges, and especially abundant in eukaryotic proteins. However, their specific evolutionary and functional scenarios are still poorly understood. Identifying AARs in protein sequences is the first step for the further investigation of their biological function and evolutionary mechanism. In principle, this is an NP-hard problem, as most of the repeat fragments are shaped by a series of sophisticated evolutionary events and become latent periodical patterns. It is not possible to define a uniform criterion for detecting and verifying various repeat patterns. Instead, different algorithms based on different strategies have been developed to cope with different repeat patterns. In this review, we attempt to describe the amino acid repeat-detection algorithms currently available and compare their strategies based on an in-depth analysis of the biological significance of protein repeats.
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