Suppression of <i>TREX1</i> deficiency-induced cellular senescence and interferonopathies by inhibition of DNA damage response

TREX1 encodes a major DNA exonuclease and mutations of this gene are associated with type I interferonopathies in human. Mice with Trex1 deletion or mutation have shortened life spans accompanied by a senescence-associated secretory phenotype. However, the contribution of cellular senescence in TREX1 deficiency-induced type I interferonopathies remains unknown. We found that features of cellular senescence present in Trex1−/− mice are induced by multiple factors, particularly DNA damage. The cGAS-STING and DNA damage response pathways are required for maintaining TREX1 deletion-induced cellular senescence. Inhibition of the DNA damage response, such as with Checkpoint kinase 2 (CHK2) inhibitor, partially alleviated progression of type I interferonopathies and lupus-like features in the mice. These data provide insights into the initiation and development of type I interferonopathies and lupus-like diseases, and may help inform the development of targeted therapeutics

Baicalin-modified polyethylenimine for miR-34a efficient and safe delivery

The security and efficiency of gene delivery vectors are inseparable for the successful construction of a gene delivery vector. This work provides a practical method to construct a charge-regulated, hydrophobic-modified, and functionally modified polyethylenimine (PEI) with effective gene delivery and perfect transfection performance through a condensation reaction, named BA-PEI. The carrier was shown to possess a favorable compaction of miRNAs into positively charged nanoparticles with a hydrodynamic size of approximately 100 nm. Additionally, BA-PEI possesses perfect degradability, which benefits the release of miR-34a from the complexes. In A549 cells, the expression level of the miR-34a gene was checked by Western blotting, which reflects the transfection efficiency of BA-PEI/miR-34a. When miR-34a is delivered to the cell, the perfect anti-tumor ability of the BA-PEI/miR-34a complex was systematically evaluated with the suppressor tumor gene miR-34a system in vitro and in vivo. BA-PEI-mediated miR-34a gene transfection is more secure and effective than the commercial transfection reagent, thus providing a novel approach for miR-34a-based gene therapy

Freezing of gait in Parkinson’s disease with glucocerebrosidase mutations: prevalence, clinical correlates and effect on quality of life

ObjectivesMutations in glucocerebrosidase (GBA1) can change the clinical phenotype of Parkinson’s disease (PD). This study aimed to explore the clinical characteristics of freezing of gait (FOG) in PD patients with GBA1 mutations.MethodsA whole-exome sequencing analysis was used to identify the GBA1 mutations (pathogenic or likely pathogenic) and exclude other PD-related gene mutations. A forward binary logistic regression model was conducted to identify the associated factors of FOG. The stepwise multiple linear regression analysis models were used to explore the effect of FOG on quality of life.ResultsThe prevalence of FOG in patients with GBA1 mutations (30/95, 31.6%) was significantly higher than those in patients without GBA1 mutations (152/760, 20%) (p = 0.009). A higher (i.e., worse) Unified PD Rating Scale part III score (OR = 1.126, 95%CI = 1.061–1.194, p &lt; 0.001) and a lower (i.e., worse) Montreal Cognitive Assessment score (OR = 0.830, 95%CI = 0.713–0.967, p = 0.017) were significantly associated with FOG in PD patients with GBA1 mutations. The presence of FOG was significantly associated with the decreased (i.e., worse) score of PD Questionnaire 39 after adjustment for sex, age, disease duration, motor score, and non-motor score (B = 14.981, p = 0.001).ConclusionFOG is a relatively common disabling symptom in PD patients with GBA1 mutations, which is affected by motor disability and cognitive decline. Quality of life is reduced in patients with FOG and GBA1 mutations

Stability and Coexistence of a Diffusive Predator-Prey System with Nonmonotonic Functional Response and Fear Effect

This paper investigates the diffusive predator-prey system with nonmonotonic functional response and fear effect. Firstly, we discussed the stability of the equilibrium solution for a corresponding ODE system. Secondly, we established a priori positive upper and lower bounds for the positive solutions of the PDE system. Thirdly, sufficient conditions for the local asymptotical stability of two positive equilibrium solutions of the system are given by using the method of eigenvalue spectrum analysis of linearization operator. Finally, the existence and nonexistence of nonconstant positive steady states of this reaction-diffusion system are established by the Leray–Schauder degree theory and Poincaré inequality

Dynamic change of water level in flood season and sediment regulation in the Three Gorges Reservoir

Based on the operation requirements of flood control, navigation, power generation, flood resource utilization and sediment reduction, this paper developed the schemes with dynamic change of water level at different periods in flood season, and focused on the response relationship between the different schemes with dynamic change of water level in flood season and the change of sediment erosion under the new water and sediment and the measured water and sediment conditions. The results indicate that the total sedimentation volume and the sedimentation volume above elevation 145m are basically about twice that of the new water and sediment series, since the amount of sand entering the reservoir in 2003-2012 is basically twice that of the new flow water and sediment series. Regardless of the type of water and sediment series, the scheme with dynamic change of water level is better than the preliminary design expectation in terms of reservoir siltation and storage capacity loss

A Design of Electromagnetic Velocity Sensor with High Sensitivity Based on Dual-Magnet Structure

The most permanent magnets in current electromagnetic velocity sensors are magnet cylinders that have been axially magnetized, with magnetic boots changing the propagation direction of the magnetic induction lines of the magnet cylinders. However, the magnetic field generated by the magnet cylinders is not fully utilized, which leads to uneven magnetic field intensity of the working air-gap and high magnetic field intensity of the nonworking air-gap. We propose a novel dual-magnet structure (DM) mainly consisting of two magnet loops that are magnetized radially and a magnetic conductive shaft, adopting a concentric nested configuration. The dual-magnet structure can make the magnetic induction lines enter the working air-gap directly from the magnet and increase the effective magnetic field, which is perpendicular to the coils in the working air-gap. This design can further improve the sensitivity of a velocity sensor and enhance its ability to detect weak signals in microtremor exploration. The validity of the dual-magnet structure has been established by numerical simulations and verified by experiments. The results reveal that the magnetic field intensity is increased by 29.18% and the sensitivity is improved by 23.9%, when the total volume and material of the magnet are unchanged. The full utilization of the material is achieved without increasing the complexity of the structure

Further insight into systemic sclerosis from the vasculopathy perspective

Systemic sclerosis (SSc) is an autoimmune disease characterized by immune dysfunction, vascular system dysfunction, and tissue fibrosis. Vascular injury, vascular remodeling, and endothelial dysfunction are the hallmark pathological changes of the disease. In the early stages of SSc development, endothelial cell injury and apoptosis can lead to vascular and perivascular inflammation, oxidative stress, and tissue hypoxia, which can cause clinical manifestations in various organs from the skin to the parenchymal organs. Early diagnosis and rational treatment can improve patient survival and quality of life. Ancillary examinations such as nailfold capillaroscopy as well as optical coherence tomography can help early detect vascular injury in SSc patients. Studies targeting the mechanisms of vascular lesions will provide new perspectives for treatment of SSc

Effect of tungsten doping on the irradiation resistance of FeCrV-based refractory medium entropy alloy for potential nuclear applications

Given the increasing demand for energy and the rising cost of fossil fuels, the development of nuclear fission and fusion reactors has become a key priority. Recently, High Entropy Alloys (HEAs) and Medium Entropy Alloys (MEAs) have emerged as promising materials for use in nuclear reactors due to their unique properties, which include significant lattice distortion, high configurational entropy, reduced diffusivity, and the cocktail effect. In this study, we designed and analysed a series of FeCrV-based Refractory Medium-entropy Alloys (RMEAs) as structural materials in fusion reactors, using Density Functional Theory. By calculating the empirical parameters, we have verified the solid solution\u27s structure stability of the FeCrV-based RMEA. We examined the mechanical, electronic, and irradiation resistance properties of these alloys and found that the incorporation of tungsten dopants could enhance both the mechanical properties and irradiation resistance of the materials, with the optimal doping level being approximately 8% of Tungsten. Furthermore, electronic structure calculations were performed to elucidate the underlying mechanisms. This knowledge can guide the development of new HEA/MEA materials for use in nuclear reactors

Meta-Analytic Review of High Anxiety Comorbidity among Patients with Vitiligo

Background. Vitiligo is a disfiguring skin disease with profound psychosocial impacts, such as anxiety, but the reported effect sizes of associations vary. We aimed to conduct a meta-analysis to quantify the strength of association between anxiety and vitiligo and to estimate the prevalence of anxiety among individuals with vitiligo. Methods. A systematic literature search was performed in five online databases (MEDLINE, Embase, Web of Science, Cochrane Library, and PsycINFO) from inception until March 20, 2020. All of the eligible studies were comprehensively reviewed, and all of the available data were analyzed according to our predefined criteria. Results. Twenty-one studies involving 3259 patients in 11 countries were included in this meta-analysis. Compared with the healthy control group, patients with vitiligo often had concomitant anxiety (OR=6.14 [95% CI: 3.35–11.24], I2=30.1%). The pooled prevalence of anxiety in female patients was significantly higher than that in males (OR=2.24 [95% CI: 1.31–3.84], I2=0.0%). Subgroup analysis showed that the pooled prevalence of clinical anxiety disorder and anxiety symptoms was 12% (95% CI: 7%–16%, I2=76.3%) and 34% (95% CI: 21%–46%, I2=94.7%), respectively. No publication bias has been detected by Begg’s funnel plot and Egger’s test. Conclusion. Patients with vitiligo have high anxiety comorbidity, with female predominance. Dermatologists and psychiatrists should be vigilant to the presence of anxiety, apply appropriate interventions to reduce the psychological impacts in a timely manner, and thus promote recovery in vitiligo patients. However, due to some objective limitations (poor information about the OR and diversity in assessment tools among included studies), findings should be interpreted with caution