Dear Editor, Lysine crotonylation is a posttranslational modifi- cation （PTM） of histone proteins originally identified by Tan et al. 1. This novel evolutionarily conserved histone modification was ...identified on 28 lysine sites on various histones 1. Lysine crotonylation occurs primar- ily on the ε-amino group of lysine, but its planar orien- tation and four-carbon length distinguish it from lysine acetylation. Histone crotonylation specifically labels the enhancers and transcription starting sites of active genes in both the human somatic cell genome and the murine male germ cell genome. Histone crotonylation, like acetylation.
How cancer cells cope with high levels of replication stress during rapid proliferation is currently unclear. Here, we show that macrophage migration inhibitory factor (MIF) is a 3' flap nuclease ...that translocates to the nucleus in S phase. Poly(ADP-ribose) polymerase 1 co-localizes with MIF to the DNA replication fork, where MIF nuclease activity is required to resolve replication stress and facilitates tumor growth. MIF loss in cancer cells leads to mutation frequency increases, cell cycle delays and DNA synthesis and cell growth inhibition, which can be rescued by restoring MIF, but not nuclease-deficient MIF mutant. MIF is significantly upregulated in breast tumors and correlates with poor overall survival in patients. We propose that MIF is a unique 3' nuclease, excises flaps at the immediate 3' end during DNA synthesis and favors cancer cells evading replication stress-induced threat for their growth.
In this study, we investigated the effects of Cu doping on the performance of CoFeSiB amorphous microwires as the core of a fluxgate magnetometer. The noise performance of fluxgate sensors primarily ...depends on the crystal structure of constituent materials. CoFeSiB amorphous microwires with varying Cu doping ratios were prepared using melt-extraction technology. The microstructure of microwire configurations was observed using transmission electron microscopy, and the growth of nanocrystalline was examined. Additionally, the magnetic performance of the microwire and the noise of the magnetic fluxgate sensors were tested to establish the relationship between Cu-doped CoFeSiB amorphous wires and sensor noise performance. The results indicated that Cu doping triggers a positive mixing enthalpy and the reduced difference in the atomic radius that enhances the degree of nanocrystalline formation within the system; differential scanning calorimetry analysis indicates that this is due to Cu doping reducing the glass formation capacity of the system. In addition, Cu doping affects the soft magnetic properties of amorphous microwires, with 1% low-doping samples exhibiting better soft magnetic properties. This phenomenon is likely the result of the interaction between nanocrystalline organization and magnetic domains. Furthermore, a Cu doping ratio of 1% yields the best noise performance, aligning with the trend observed in the material's magnetic properties. Therefore, to reduce the noise of the CoFeSiB amorphous wire sensor, the primary goal should be to reduce microscopic defects in amorphous alloys and enhance soft magnetic properties. Cu doping is a superior preparation method which facilitates control over preparation conditions, ensuring the formation of stable amorphous wires with consistent performance.
This article presents a Lyapunov precise integral-based analysis method for seismic structures with added viscous fluid dampers. This study uses the full stress algorithm as the optimization method, ...considering the mean square of interstory drifts as the optimization objective, the position of the damper as the optimization object, and the random vibration analysis method as the calculation method to optimize seismic frame structures with viscous dampers. A precise integral solution is derived for the Lyapunov equation based on the general expression of the Lyapunov differential equation for the damping system under the excitation of a nonstationary stochastic process using two types of modulation functions: g(t)=1 and g(t)=t. Finally, the optimal damping arrangement is achieved using this method with a six-layer non-eccentric planar frame. In addition, the optimization results of this study are verified with those in the literature using time-history analysis, which verifies the feasibility and effectiveness of the proposed method. This study provides a method for the optimal configuration of dampers for seismic response of structures, which is beneficial for engineering applications and the protection of seismic structures.
Large tumor suppressor 1 (LATS1) is the key kinase controlling activation of Hippo signalling pathway. Post-translational modifications of LATS1 modulate its kinase activity. However, detailed ...mechanism underlying LATS1 stability and activation remains elusive. Here we report that LATS1 is acetylated by acetyltransferase CBP at K751 and is deacetylated by deacetylases SIRT3 and SIRT4. Acetylation at K751 stabilized LATS1 by decreasing LATS1 ubiquitination and inhibited LATS1 activation by reducing its phosphorylation. Mechanistically, LATS1 acetylation resulted in inhibition of YAP phosphorylation and degradation, leading to increased YAP nucleus translocation and promoted target gene expression. Functionally, LATS1-K751Q, the acetylation mimic mutant potentiated lung cancer cell migration, invasion and tumor growth, whereas LATS1-K751R, the acetylation deficient mutant inhibited these functions. Taken together, we demonstrated a previously unidentified post-translational modification of LATS1 that converts LATS1 from a tumor suppressor to a tumor promoter by suppression of Hippo signalling through acetylation of LATS1.
During long-duration dynamic loads, such as wind loads or seismic effects, the internal temperature and pressure of a damping cylinder escalate rapidly, which induce shifts in the mechanical ...attributes of viscous fluid dampers (VFDs). This study investigated the mechanical performance of VFD considering the coupling effects of temperature and pressure under long-duration loads. First, we analyzed the mechanical and energy-dissipation performances of the dampers based on the dynamic mechanical tests considering different loading frequencies, displacement amplitude, and loading cycles. The experimental results indicated that both temperature and pressure influenced the output of the dampers, and in the sealed environment of the damper pip, temperature and pressure exerted mutual influence. Furthermore, the relationship between the damping coefficient and temperature–pressure coupling effects was obtained. Subsequently, an improved mathematical model for the mechanical performance of a gap-type VFD was proposed by considering the macroscopic energy balance of the entire fluid within the damper. Finally, the accuracy of the mathematical model for VFD under long-duration dynamic loads was validated by comparing the computational results with the experimental data.
Purpose
For patients with intractable cancer-related pain, administration of strong opioid analgesics and adjuvant agents by the intrathecal (i.t.) route in close proximity to the target ...receptors/ion channels, may restore pain relief. Hence, the aim of this study was to use bioerodable polymers to encapsulate an opioid analgesic (hydromorphone) and an adjuvant drug (ketamine) to produce prolonged-release formulations for i.t. injection.
Methods
A two-stage microfluidic method was used to fabricate nanoparticles (NPs). The physical properties were characterised using dynamic light scattering and transmission electron microscopy. A pilot
in vivo
study was conducted in a rat model of peripheral neuropathic pain.
Results
The
in vitro
release of encapsulated payload from NPs produced with a polymer mixture (CPP-SA/PLGA 50:50) was sustained for 28 days. In a pilot
in vivo
study, analgesia was maintained over a three day period following i.t. injection of hydromorphone-loaded NPs at 50 μg. Co-administration of ketamine-loaded NPs at 340 μg did not increase the duration of analgesia significantly.
Conclusions
The two-stage microfluidic method allowed efficient production of analgesic/adjuvant drug-loaded NPs. Our proof-of-principle
in vivo
study shows prolonged hydromorphone analgesic for 78 h after single i.t. injection. At the i.t. dose administered, ketamine released from NPs was insufficient to augment hydromorphone analgesia.
The accurate prediction of nonlinear structural behaviors under different seismic intensities is an important basis for seismic resilience assessments of building structures. The moment–rotation ...relationship is often used to characterize the seismic performance of connections, and is widely used in high-efficiency nonlinear structural analysis. In this paper, a method of calculating the curve using a four-linear equivalent model is presented, aiming to quantify the characteristic point parameters of the moment–rotation curves of monolithic precast beam–column (MPBC) connections for engineering design purposes. The method considered the contribution of the elastic flexure of beams and columns, the relative slip of beam longitudinal bars in the core zone, and the formation of plastic hinges at beam ends to the total deflection. Due to the presence of local complex configurations in MPBC connections, the fine fiber section method was used for moment–curvature analysis of critical beam sections. The determination of the sectional analysis processes was controlled by the strain of steel bars or concrete or their coupling effect. In addition, a two-step method was proposed to construct the moment–rotation relationship of cruciform beam–column connections for solving the deformation compatibility of beams on both sides of the column caused by asymmetric reinforcement and the strength difference between new and old concrete. To reflect the current manufacturing level of MPBC connections, 58 representative specimens reported in recent years were analyzed and classified as type 1–5. All types of MPBC connections and their 18 cast-in situ counterparts were calculated using the proposed method for both verification and quantification. The verification showed that the proposed method had good applicability to both cast-in situ and precast beam–column connections. The quantification showed that the characteristic point parameters were slightly different between these two connections. Accordingly, modification coefficients were suggested for MPBC connections to facilitate design.
In glucose transporter 1 deficiency syndrome (Glut1DS), glucose transport into brain is reduced due to impaired Glut1 function in endothelial cells at the blood–brain barrier. This can lead to ...shortages of glucose in brain and is thought to contribute to seizures. Ketogenic diets are the first‐line treatment and, among many beneficial effects, provide auxiliary fuel in the form of ketone bodies that are largely metabolized by neurons. However, Glut1 is also the main glucose transporter in astrocytes. Here, we review data indicating that glucose shortage may also impact astrocytes in addition to neurons and discuss the expected negative biochemical consequences of compromised astrocytic glucose transport for neurons. Based on these effects, auxiliary fuels are needed for both cell types and adding medium chain triglycerides (MCTs) to ketogenic diets is a biochemically superior treatment for Glut1DS compared to classical ketogenic diets. MCTs provide medium chain fatty acids (MCFAs), which are largely metabolized by astrocytes and not neurons. MCFAs supply energy and contribute carbons for glutamine and γ‐aminobutyric acid synthesis, and decanoic acid can also block α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid glutamate receptors. MCTs do not compete with metabolism of ketone bodies mostly occurring in neurons. Triheptanoin, an anaplerotic but also gluconeogenic uneven MCT, may be another potential addition to ketogenic diets, although maintenance of “ketosis” can be difficult. Gene therapy has also targeted both endothelial cells and astrocytes. Other approaches to increase fuel delivery to the brain currently investigated include exchange of Glut1DS erythrocytes with healthy cells, infusion of lactate, and pharmacological improvement of glucose transport. In conclusion, although it remains difficult to assess impaired astrocytic energy metabolism in vivo, astrocytic energy needs are most likely not met by ketogenic diets in Glut1DS. Thus, we propose prospective studies including monitoring of blood MCFA levels to find optimal doses for add‐on MCT to ketogenic diets and assessing of short‐ and long‐term outcomes.
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