The pathogenic mechanism of TAR DNA-binding protein 43(TDP-43)in amyotrophic lateral sclerosis

The onset of amyotrophic lateral sclerosis is usually characterized by focal death of both upper and/or lower motor neurons occurring in the motor cortex,basal ganglia,brainstem,and spinal cord,and commonly involves the muscles of the upper and/or lower extremities,and the muscles of the bulbar and/or respiratory regions.However,as the disease progresses,it affects the adjacent body regions,leading to generalized muscle weakness,occasionally along with memory,cognitive,behavioral,and language impairments;respiratory dysfunction occurs at the final stage of the disease.The disease has a complicated pathophysiology and currently,only riluzole,edaravone,and phenylbutyrate/taurursodiol are licensed to treat amyotrophic lateral sclerosis in many industrialized countries.The TAR DNA-binding protein 43 inclusions are observed in 97%of those diagnosed with amyotrophic lateral sclerosis.This review provides a preliminary overview of the potential effects of TAR DNAbinding protein 43 in the pathogenesis of amyotrophic lateral sclerosis,including the abnormalities in nucleoplasmic transport,RNA function,post-translational modification,liquid-liquid phase separation,stress granules,mitochondrial dysfunction,oxidative stress,axonal transport,protein quality control system,and non-cellular autonomous functions(e.g.,glial cell functions and prion-like propagation).

Nicotinamide adenine dinucleotide treatment confers resistance to neonatal ischemia and hypoxia:effects on neurobehavioral phenotypes

Neonatal hypoxic-ischemic brain injury is the main cause of hypoxic-ischemic encephalopathy and cerebral palsy.Currently,there are few effective clinical treatments for neonatal hypoxic-ischemic brain injury.Here,we investigated the neuroprotective and molecular mechanisms of exogenous nicotinamide adenine dinucleotide,which can protect against hypoxic injury in adulthood,in a mouse model of neonatal hypoxic-ischemic brain injury.In this study,nicotinamide adenine dinucleotide(5 mg/kg)was intraperitoneally administered 30 minutes befo re surgery and every 24 hours thereafter.The results showed that nicotinamide adenine dinucleotide treatment improved body weight,brain structure,adenosine triphosphate levels,oxidative damage,neurobehavioral test outcomes,and seizure threshold in experimental mice.Tandem mass tag proteomics revealed that numerous proteins were altered after nicotinamide adenine dinucleotide treatment in hypoxic-ischemic brain injury mice.Parallel reaction monitoring and western blotting confirmed changes in the expression levels of proteins including serine(or cysteine)peptidase inhibitor,clade A,member 3N,fibronectin 1,5'-nucleotidase,cytosolic IA,microtubule associated protein 2,and complexin 2.Proteomics analyses showed that nicotinamide adenine dinucleotide ameliorated hypoxic-ischemic injury through inflammation-related signaling pathways(e.g.,nuclear factor-kappa B,mitogen-activated protein kinase,and phosphatidylinositol 3 kinase/protein kinase B).These findings suggest that nicotinamide adenine dinucleotide treatment can improve neurobehavioral phenotypes in hypoxic-ischemic brain injury mice through inflammation-related pathways.

Pathological mechanisms of amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis refers to a neurodegenerative disease involving the motor system,the cause of which remains unexplained despite several years of research.Thus,the journey to understanding or treating amyotrophic lateral sclerosis is still a long one.According to current research,amyotrophic lateral sclerosis is likely not due to a single factor but rather to a combination of mechanisms mediated by complex interactions between molecular and genetic pathways.The progression of the disease involves multiple cellular processes and the interaction between different complex mechanisms makes it difficult to identify the causative factors of amyotrophic lateral sclerosis.Here,we review the most common amyotrophic lateral sclerosis-associated pathogenic genes and the pathways involved in amyotrophic lateral sclerosis,as well as summarize currently proposed potential mechanisms responsible for amyotrophic lateral sclerosis disease and their evidence for involvement in amyotrophic lateral sclerosis.In addition,we discuss current emerging strategies for the treatment of amyotrophic lateral sclerosis.Studying the emergence of these new therapies may help to further our understanding of the pathogenic mechanisms of the disease.

Reduction of the oxidative damage to H_(2)O_(2)-induced HepG2 cells via the Nrf2 signalling pathway by plant flavonoids Quercetin and Hyperoside

Hyperoside and quercetin are similar in molecular structures.In this study,the antioxidant regulatory targets of hyperoside and quercetin are mainly in the nuclear factor(erythroid-2-derived)-related factor 2(Nrf2)pathway predicted by network pharmacology.And the antioxidant effect and mechanism of hyperoside and quercetin were measured and compared in H_(2)O_(2)-induced Hep G2 cells and Caenorhabditis elegans.The findings indicated that quercetin was more effective than hyperoside in reducing oxidative damage,which was proved by improved cell viability,decreased reactive oxygen species(ROS)production,decreased cellular apoptosis,and alleviated mitochondrial damage.In addition,quercetin was more efficient than hyperoside in enhancing the expression of Nrf2-associated m RNAs,increasing the activities of superoxide dismutase(SOD),glutathione peroxidase(GSH-Px),and catalase(CAT),and reducing the cellular malondialdehyde(MDA)content.Quercetin was superior to hyperoside in prolonging the lifespan of worms,decreasing the accumulation of lipofuscin,inhibiting ROS production,and increasing the proportion of skn-1 in the nucleus.With the Nrf2 inhibitor ML385,we verified that quercetin and hyperoside primarily protected the cells against oxidative damage via the Nrf2 signalling pathway.Furthermore,molecular docking and dynamics simulations demonstrated that the quercetin-Kelch-like ECH-associated protein 1(Keap1)complex was more stable than the hyperoside-Keap1 complex.The stable structure of the complex might hinder the binding of Nrf2 and Keap1 to release Nrf2 and facilitate its entry into the nucleus to play an antioxidant role.Overall,quercetin had a better antioxidant than hyperoside.

Direct visualization of laser-driven dynamic fragmentation in tin by in situ x-ray diffraction

We present a novel method for investigating laser-driven dynamic fragmentation in tin using in situ X-ray diffraction.Our experimental results demonstrate the feasibility of the method for simultaneously identifying the phase and temperature of fragments through analysis of the diffraction pattern.Surprisingly,we observe a deviation from the widely accepted isentropic release assumption,with the temperature of the fragments being found to be more than 100 K higher than expected,owing to the release of plastic work during dynamic fragmentation.Our findings are further verified through extensive large-scale molecular dynamics simulations,in which strain energies are found to be transferred into thermal energies during the nucleation and growth of voids,leading to an increase in temperature.Our findings thus provide crucial insights into the impact-driven dynamic fragmentation phenomenon and reveal the significant influence of plastic work on material response during shock release.

Atomically bonding Na anodes with metallized ceramic electrolytes by ultrasound welding for high-energy/power solid-state sodium metal batteries

A solid-state sodium metal battery has cut a striking figure in next-generation large-scale energy storage technology on account of high safety,high energy density,and low cost.Nevertheless,the large interfacial resistance and sodium dendrite growth originating from the poor interface contact seriously hinder its practical application.Herein,a modified ultrasound welding was proposed to atomically bond Na anodes and Au-metalized Na_(3)Zr_(2)Si_(2)PO_(12) electrolytes associated with the in situ formation of Na–Au alloy interlayers.Thereupon,intimate Na_(3)Zr_(2)Si_(2)PO_(12)-Au/Na interfaces with a low interfacial resistance(~23Ωcm^(2))and a strong dendrite inhibition ability were constructed.The optimized Na symmetric battery can cycle steadily for more than 900 h at 0.3 mA cm^(-2) under a low overpotential(<50 mV)of Na electroplating/stripping and deliver a high critical current density of 0.8 mAcm^(-2) at room temperature.By incorporating the above interface into the solid-state Na metal battery,taking three-dimensional Na_(3)V_(2)(PO_(4))_(3) as the cathode,the full battery offers a high energy density of 291 Wh kg^(-1) at a high power density of 1860Wkg^(-1).A pouch-type solid-state sodium metal full battery based on a ceramic electrolyte was assembled for the first time,and it lit a 3 V LED lamp.Such a strategy of the ultrasound welding metalized solid-state electrolyte/Na interface by engineering the Na-Au interlayer would pave a new pathway to engineer a low-resistance and highly stable interface for high-energy/density solid-state sodium metal batteries.

Analysis of Compliance Management Practice of American Drug Registration Applicants and Its Enlightenment to China

In order to achieve the goal of drug safety, effectiveness and quality control, corporate compliance management construction is significant. Therefore, this paper systematically analyzes the seven elements of compliance management for U.S. pharmaceutical manufacturers as described in the Compliance Program Guidance for Pharmaceutical Manufacturers issued by the HHS-Office of Inspector General, as well as further analyzes the implementation of the guidance by representative multinational companies in different drug registration stages. Finally, some suggestions and implications are proposed to strengthen the construction of compliance management for Chinese drug registration applicants based on the former practical experience.

细菌GntR家族转录调控因子的研究进展

GntR家族转录调控因子是细菌中分布最为广泛的一类螺旋–转角–螺旋(helix-turn-helix,HTH)转录调控因子,此家族转录调控因子包含两个功能域,分别是N端的DNA结合结构域和C端的效应物结合结构域/寡聚化作用结构域。DNA结合结构域的氨基酸序列是非常保守的,但效应物结合结构域/寡聚化作用结构域的氨基酸序列却存在很大的差异性。目前许多GntR家族的转录调控因子已经被鉴定,这些转录因子调控细菌许多不同的细胞过程,如运动性、葡萄糖代谢、细菌的耐药性、病原细菌的致病力等。本文主要阐述了GntR家族转录调控因子的发现、二级结构、生物学功能、调控模式等方面的研究进展,旨在为研究者全面、深入地了解GntR家族转录调控因子的功能及作用机理提供帮助。

Postoperative chemotherapy with S-1 plus oxaliplatin versus S-1alone in locally advanced gastric cancer(RESCUE-GC study): a protocol for a phase Ⅲ randomized controlled trial

Background： The ACTS-GC study had shown postoperative adiuvant therapy with S-1 improved survival of patients with locally advanced gastric cancer. Addition of oxaliplatin to S-1 is considered to be acceptable as one of the treatment options for gastric cancer patients after radical gastrectomy with D2 lymph node excision. Methods： We have commenced a randomized phase III trial in December 2016 to evaluate S-I plus oxaliplatin compared with S-1 alone in the adjuvant setting for locally advanced gastric cancer. A total of 564 patients will be accrued from 13 Chinese institutions in two years. The primary endpoint is 3-year relapse-free survival. The secondary endpoints are 5-year overall survival, proportion of patients who complete the postoperative chemotherapy and incidence of adverse events. Ethic and dissemination： The trial has been approved by the institutional review board of each participating institution and it was activated on December, 2016. The enrollment will be finished in December, 2018. Patient＇s follow-up will be ended until December, 2023. Trial registration： ClinicalTrials.gov, identifier： NCT02867839. Registered on August 4, 2016.

Mandible exosomal ssc-mir-133b regulates tooth development in miniature swine via endogenous apoptosis

Signal transduction between different organs is crucial in the normal development of the human body. As an important medium for signal communication, exosomes can transfer important information, such as microRNAs(miRNAs), from donors to receptors.MiRNAs are known to fine-tune a variety of biological processes, including maxillofacial development; however, the underlying mechanism remains largely unknown. In the present study, transient apoptosis was found to be due to the expression of a miniature swine maxillofacial-specific miRNA, ssc-mir-133b. Upregulation of ssc-mir-133b resulted in robust apoptosis in primary dental mesenchymal cells in the maxillofacial region. Cell leukemia myeloid 1(Mcl-1) was verified as the functional target, which triggered further downstream activation of endogenous mitochondria-related apoptotic processes during tooth development.More importantly, mandible exosomes were responsible for the initial apoptosis signal. An animal study demonstrated that ectopic expression of ssc-mir-133 b resulted in failed tooth formation after 12 weeks of subcutaneous transplantation in nude mice. The tooth germ developed abnormally without the indispensable exosomal signals from the mandible.

MiR-378a-3p acts as a tumor suppressor in gastric cancer via directly targeting RAB31 and inhibiting the Hedgehog pathway proteins GLI1/2

Objective:To improve the prognosis of patients with gastric cancer(GC),more effective therapeutic targets are urgently needed.Increasing evidence indicates that miRNAs are involved in the progression of various tumors,and RAS-associated protein in the brain 31(RAB31)is upregulated and promotes the progression of multiple malignant tumors.Here,we focused on identifying RAB31-targeted miRNAs and elucidating their potential mechanism in the progression of GC.Methods:RAB31 and miR-378a-3p expression levels were detected in paired fresh GC tissues and GC cell lines.Bioinformatics analysis was used to predict the miRNAs targeting RAB31 and the relationships between RAB31 and other genes.Dual-luciferase reporter assays were applied to verify the targeted interaction relationship.CCK-8,colony formation,flow cytometry,wound healing,and Transwell assays were performed to assess the proliferation,apoptosis,migration,and invasion of GC cells.Tumorsphere formation assays were performed to assess the stemness of gastric cancer stem cells.Related proteins were detected by Western blot.Xenograft assays in nude mice were performed to explore the effect of miR-378a-3p in vivo.Results:We report the first evidence that miR-378a-3p is downregulated in GC,whereas its overexpression inhibits proliferation,invasion,and migration as well as promotes apoptosis in GC cells.Mechanistically,miR-378a-3p inhibits the progression of GC by directly targeting RAB31.Restoring RAB31 expression partially offsets the inhibitory effect of miR-378a-3p.Further research revealed that miR-378a-3p inhibits GLI1/2 in the Hedgehog signaling pathway and attenuates the stemness of gastric cancer stem cells.Finally,xenograft assays showed that miR-378a-3p inhibits GC tumorigenesis in vivo.Conclusions:MiR-378a-3p inhibits GC progression by directly targeting RAB31 and inhibiting the Hedgehog signaling pathway proteins GLI1/2.

Dental stem cell-derived extracellular vesicles transfer miR-330-5p to treat traumatic brain injury by regulating microglia polarization

Traumatic brain injury(TBI)contributes to the key causative elements of neurological deficits.However,no effective therapeutics have been developed yet.In our previous work,extracellular vesicles(EVs)secreted by stem cells from human exfoliated deciduous teeth(SHED)offered new insights as potential strategies for functional recovery of TBI.The current study aims to elucidate the mechanism of action,providing novel therapeutic targets for future clinical interventions.With the mi RNA array performed and Real-time PCR validated,we revealed the crucial function of mi R-330-5p transferred by SHED-derived EVs(SHED-EVs)in regulating microglia,the critical immune modulator in central nervous system.Mi R-330-5p targeted Ehmt2 and mediated the transcription of CXCL14 to promote M2 microglia polarization and inhibit M1 polarization.Identified in our in vivo data,SHED-EVs and their effector mi R-330-5p alleviated the secretion of inflammatory cytokines and resumed the motor functional recovery of TBI rats.In summary,by transferring mi R-330-5p,SHED-EVs favored anti-inflammatory microglia polarization through Ehmt2 mediated CXCL14transcription in treating traumatic brain injury.

Additional Mass: Orthotropic Membrane Material with Four Sides Fixed in Air Flow

When the membrane material in the air field vibrates, it will drive the movement of the surrounding air. The aerodynamic force generated by the moving air will act on the membrane material in turn, resulting in the change of dynamic characteristics such as membrane vibration frequency. In this paper, the additional air mass produced by membrane vibration in air is studied. Firstly, under the assumption that the incoming flow is uniform and incompressible ideal potential flow, the additional air mass acting on the surface is derived by using the thin airfoil theory and potential flow theory respectively. Then, according to the first law of thermodynamics and the principle of aeroelasticity, the analytical expression of the additional air mass is derived. Finally, through a specific example, the variation of the additional air mass with the membrane material parameters and pretension, as well as the influence of the aerodynamic force on the vibration frequency and amplitude of the membrane is obtained.

Research at Tsinghua University on electrical explosions of wires

Electrical explosion of a wire(EEW)has been investigated for more than ten years at Tsinghua University,and the main results are reviewed in this paper.Based onEEWin vacuum,an X-pinch was used as an x-ray source for phase-contrast imaging of small insects such as mosquitoes and ants in which it was possible to observe clearly their detailed internal structures,which can never be seen with conventional x-ray radiography.Electrical explosion of a wire array(EEWA)in vacuum is the initial stage in the formation of a wire-array Z-pinch.The evolution ofEEWAwas observed with x-ray backlighting using two X-pinches as x-ray sources.It was found that each wire in an EEWA exhibits a core–corona structure instead of forming a fully vaporized metallic vapor.This structure is detrimental to the plasma implosion of a Z-pinch.By inserting an insulator as a flashover switch into the cathode,formation of a core–corona structure was suppressed and core-freeEEWAwas realized.EEWin gases was used for nanopowder production.Three parameters(vaporization rate,gas pressure,and energy deposited in the exploding plasma)were found to influence the nanoparticle size.EEWin water was used for shock-wave generation.The shock wave generated by melting could be recorded with a piezoelectric gauge only in underheat EEW.ForEEW with a given stored energy but different energy-storage capacitor banks,the small capacitor bank produced a rapidly rising current that deposited more energy into the wire and generated a stronger shock wave.

预氧化对HP40合金(含铱和不含铱变种)的周期焦化和抗渗碳的影响

预氧化结果表明在高温氧化后对合金上附着的鳞片稀土元素起重要的作用。钇变种的附着较好的鳞片可以优质的循环焦化和防渗碳。这是因为能防止快速离子扩散的整体氧化铬层能延缓经预氧化的合金外部催化的焦化和内渗碳。对铸态合金已检测到严重的焦化和渗碳,也观察了预氧化试样,它的鳞片会严重剥落。

First-principles study of a new BP_(2)two-dimensional material

Two-dimensional materials have a wide range of applications in many aspects due to their unique properties. Here we carry out a detailed structural search and design of the BP2using the first principles method, and find a new PMM2 sheet.The analysis of the phonon dispersive curves shows that the 2D PMM2 is dynamic stable. The study of molecular dynamics shows that the 2D PMM2 can be stable under high temperature, even at 600 K. Most importantly, when a suitable strain is applied, the structure can exhibit other electronic properties such as direct band gap semiconductor. In addition, the small strain can tune the band gap value of the PMM2 structure to around 1.4 e V, which is very close to the ideal band gap of solar materials. Therefore, the 2D PMM2 may have potential applications in the field of photovoltaic materials.

Electron relaxation properties of Ar magnetron plasmas

An understanding of electron relaxation properties in plasmas is of importance in the application of magnetrons.An improved multi-term approximation of the Boltzmann equation is employed to study electron transport and relaxation properties in plasmas.Elastic,inelastic and nonconservative collisions between electrons and neutral particles are considered.The expressions for the transport coefficients are obtained using the expansion coefficients and the collision operator term.Numerical solutions of the matrix equations for the expansion coefficients are also investigated.Benchmark calculations of the Reid model are presented to demonstrate the accuracy of the improved multi-term approximation.It is shown that the twoterm approximation is generally not accurate enough and the magnetic fields can reduce the anisotropy of the velocity distribution function.The electron relaxation properties of Ar plasmas in magnetrons for various magnetic fields are studied.It is demonstrated that the energy parameters change more slowly than the momentum parameters.

End-on x-ray backlighting experiments for axial diagnostics of wire-array Z-pinch plasma on PPG-1

An X-pinch axial backlighting system has been designed to quantitatively measure the density distribution of wirearray Z-pinch plasmas. End-on backlighting experiments were carried out on a 200 kA, 100 ns pulsed-power generator（PPG-1） at the Tsinghua University. Compared with side-on backlighting, end-on measurements provide an axial view of the evolution of Z-pinch plasmas. Early stages of 2-, 4-, and 8-wire Z-pinch plasmas were observed via point-projection backlighting radiography with a relatively high success rate. The density distribution of Z-pinch plasma on the r–θ plane was obtained directly from the images with the help of step wedges, and the inward radial velocity was calculated. The ablation rates obtained by X-pinch backlighting experiments are compared in detail with those calculated by the rocket model and the results show consistency.

The Study of Unusual Emission from PSR B1859+07 using FAST

We present simultaneous broad-band radio observations on the abnormal emission mode from PSR B1859+07using the Five-hundred-meter Aperture Spherical radio Telescope(FAST).This pulsar shows peculiar emission,which takes the form of occasional shifts of emission to an early rotational phase and mode change of emission at the normal phase.We confirm all these three emission modes with our data sets,including the B(burst)and Q(quiet)modes of the non-shifted pulses and the emission shift mode with a quasi-periodicity of 155 pulses.We also identify a new type of emission shift event,which has emission at the normal phase during the event.We studied polarization properties of these emission modes in detail,and found that they all have similar polarization angle curve,indicating the emissions of all these three modes are from the same emission height.

An Analysis of College-graduate Village Official Policy in China

The article analyzes the target group,the objective and the main content of college-graduate village official policy. The stipulation about recruitment,obligation,training and living support concerning these village officials is analyzed in this article as well. It is obvious that the current policy targets and policy content have many advantages,but the policy makers should also find out its shortcomings at the same time. In order to cope with these shortcomings,the policy makers should readjust the policy target and construct the feedback-control mechanism of the policy.