Physiological levels of ATP negatively regulate proteasome function

Intracellular protein degradation by the ubiquitin-proteasome system is ATP dependent, and the optimal ATP concentration to activate proteasome function in vitro is -100 μM. IntraceUular ATP levels are generally in the low millimolar range, but ATP at a level within this range was shown to inhibit proteasome peptidase activities in vitro. Here, we report new evidence that supports a hypothesis that intracellular ATP at the physiological levels bidirectionally regulates 26S proteasome proteolytic function in the cell. First, we confirmed that ATP exerted bidirectional regulation on the 26S proteasome in vitro, with the optimal ATP concentration （between 50 and 100μM） stimulating proteasome chymotrypsin-like activities. Second, we found that manipulating intracellular ATP levels also led to bidirectional changes in the levels of proteasome-specific protein substrates in cultured cells. Finally, measures to increase intracellular ATP enhanced, while decreasing intraceHular ATP attenuated the ability of proteasome inhibition to induce cell death. These data strongly suggest that endogenous ATP within the physiological concentration range can exert a negative impact on proteasome activities, allowing the cell to rapidly upregulate proteasome activity on ATP reduction under stress conditions.

Cell multiplication, apoptosis and p-Akt protein expression of bone mesenchymal stem cells of rat under hypoxia environment

Objective ：To elucidate whether cell multiplication, apoptosis, glucose intake and p-Akt protein expression of bone Mesenchyreal Stem Cells（MSCs） of rats is influenced by a hypoxic environment ex vivo. Methods ：Passage 3 of bone marrow MSCs taken from Wistar rats,were cultured in a culturing chamber with 94%N2,1%O2,5%CO2 at 37℃. At different hypoxia time points ,0,0.5, 1,4 and 8 h, glucose uptake was assayed by using radiation isotope ^3H-G, Apoptotic Rate（AR） and dead rate（DR） were analyzed by flow cytometry（FCM） after Annexin V/PI staining, cell multiplication（by MTr methods） and p-Akt protein by immunocytochemistry and western blot. Results ：Assay for CD29^± ,CD44^± ,CD71^± ,CD34^-, Tn T^±（after 5-azacytidine agent inducing） and ALP^±（after bone differentiation agent inducing） suggested these bone-derived cells were MSCs. The ^3H-G intaking ratio （CPM/ flask value：157 ± 11,110 ± 11,107 ± 13,103 ± 10,100 ± 9 and 98 ± 10） of MSCs at different hypoxia time points, significantly decreased compared to that of normoxia（P 〈 0.01） and tended to descend slowly with hypoxia time duration, for which there was no statistical significance（P 〉 0.05）. The AR（0.09 ± 2.03%,12.9 ± 1.72%,13.7 ± 2.26%,13.8 ± 3.01%,14.1 ± 2.78% and 14.7 ± 4.01% at 0,0.5,1,4 and 8 h,respectively,P 〈 0.01） and DR （0.04, ± 1.79% ,0.93 ± 1.85% ,3.11 ± 2.14% ,4.09 ± 2.36% ,4.72 ± 2.05% and 4.91 ± 3.72% at 0,0.5,1,4 and 8 h, respectively, P 〈 0.05） at different hypoxia time points significantly increased compared to those time in normoxia; The AR further went up with time （P 〈 0.05）, however there was no statistical significance （P 〉 0.05） for the DR. Optical absorption value of MTr methods at different hypoxia time points significantly decreased compared to those with a corresponding normoxia time （P 〈 0.01） and degraded with time （in an hypoxic environment -P 〈 0.01）. IOD of p-Akt protein of MSCs at different hypoxia time points significantly increased （0.367 ± 0.031,0.556 ± 0.023,0.579 ± 0.013, 0.660 ± 0.024, 0.685 ± 0.039 and 0.685 ± 0.011, respectively） compared to their equivalents in normoxia （P〈0.05）, however, there was no statistical significance （P 〉 0.05） for different hypoxia time points. Hypoxia may result in ultramicrostructure changes, such as defluvium of Microvilli, apoptotic body, ＂margination＂ and so on and are further aggravated with hypoxia time stretching. Conclusion： Hypoxia may lead to a depression of MSCs intaldng glucose, creep of cell multiplication, upregulation of p-Akt protein and apoptosis of MSCs ex vivo.

Stability of liquid crystal systems doped withγ-Fe_(2)O_(3)nanoparticles

In order to explore the stability of a liquid crystal(LC)system doped withγ-Fe_(2)O_(3)nanoparticles,the physical properties(clearing point,dielectric properties),electro-optical properties and residual direct-current voltage(RDCV)of the doped LC system were measured and evaluated at different times.First,the temperature was controlled by precision hot stage,and the clearing point temperature of doped LC was observed and measured by a polarized optical microscope.Using a precision LCR meter,we measured the capacitance-voltage curves of the doped LC system at the temperature of 27℃.The dielectric constant of doped LC was calculated by the dualcell capacitance method.Then,the electro-optical properties of the doped LC system were measured.Finally,the RDCV of the doped LC system was measured and calculated.After five months,the parameters of the doped LC system were re-measured and analyzed under the same conditions to evaluate its stability.The experimental results show that,within five months,the clearing point change rate of doped LC is in the range of 0.24%-1.37%,the change of dielectric anisotropy is in the range of 0.035-0.2,the curves of electro-optical properties are basically fitted,and the change rate of saturated RDCV is about 11.2%,which basically indicate that the LC system doped withγ-Fe_(2)O_(3)nanoparticles has good stability.

Effects of Denervation on the Mid-term Results of Knee Joint Functions after Non-resurfaced Total Knee Arthroplasty

Objective:Total knee arthroplasty(TKA)has become an effective treatment modality for end-stage osteoarthritis and rheumatoid arthritis.Postoperative problems such as anterior knee pain affect postoperative patient satisfaction.Patellar denervation has been proposed as a technique to relieve pain,but its efficacy remains controversial.This study evaluated the mid-and long-term effects of patellar denervation on postoperative knee joint functions,hoping to provide better guidance for clinical practice.Methods:This study is a prospective randomized controlled double-blind study.58 patients undergoing bilateral non-resurfaced total knee arthroplasty were included and randomized into two groups.Both groups underwent total knee arthroplasty while patellar denervation was performed only on the experimental group.Information regarding whether if patellar denervation was performed were withheld from all patients and outcome assessors.All surgeries were performed by the same high-level professional physician,and the post-stable knee prosthesis system(PS Scorpio NRG PS,Stryker)was used during the surgeries.The knee joint functions were evaluated by professional assessors before and after surgery.The evaluation indicators mainly include KSS scoring,Western Ontario and McMaster Universities(WOMAC)scoring and Visual Analogue Scale(VAS),FJS scoring,etc.The follow-up period was 3 years and 5 years after surgery.Results:The experimental group had better KSS and FJS scores than the control group,the difference was statistically significant.There was no significant inter-group difference in WOMAC and VAS scores.Conclusion:The patellar denervation in TKA patients has positive effects on the mid-and long-term recovery of knee joint functions,and the postoperative satisfaction is better.

Sex difference in human diseases:mechanistic insights and clinical implications

Sex characteristics exhibit significant disparities in various human diseases,including prevalent cardiovascular diseases,cancers,metabolic disorders,autoimmune diseases,and neurodegenerative diseases.Risk profiles and pathological manifestations of these diseases exhibit notable variations between sexes.The underlying reasons for these sex disparities encompass multifactorial elements,such as physiology,genetics,and environment.Recent studies have shown that human body systems demonstrate sex-specific gene expression during critical developmental stages and gene editing processes.These genes,differentially expressed based on different sex,may be regulated by androgen or estrogen-responsive elements,thereby influencing the incidence and presentation of cardiovascular,oncological,metabolic,immune,and neurological diseases across sexes.However,despite the existence of sex differences in patients with human diseases,treatment guidelines predominantly rely on male data due to the underrepresentation of women in clinical trials.At present,there exists a substantial knowledge gap concerning sex-specific mechanisms and clinical treatments for diverse diseases.Therefore,this review aims to elucidate the advances of sex differences on human diseases by examining epidemiological factors,pathogenesis,and innovative progress of clinical treatments in accordance with the distinctive risk characteristics of each disease and provide a new theoretical and practical basis for further optimizing individualized treatment and improving patient prognosis.

Transcription factor ETV4 promotes the development of hepatocellular carcinoma by driving hepatic TNF-αsignaling

Background Hepatic inflammation is the major risk factor of hepatocellular carcinoma(HCC).However,the underlying mechanism by which hepatic inflammation progresses to HCC is poorly understood.This study was designed to investigate the role of ETS translocation variant 4(ETV4)in linking hepatic inflammation to HCC.Methods Quantitative real-time PCR and immunoblotting were used to detect the expression of ETV4 in HCC tissues and cell lines.RNA sequencing and luciferase reporter assays were performed to identify the target genes of ETV4.Hepatocyte-specific ETV4-knockout(ETV4fl/fl,alb-cre)and transgenic(ETV4Hep-TG)mice and diethylnitrosamine-carbon tetrachloride(DEN-CCL4)treatment experiments were applied to investigate the function of ETV4 in vivo.The Cancer Genome Atlas(TCGA)database mining and pathological analysis were carried out to determine the correlation of ETV4 with tumor necrosis factor-alpha(TNF-α)and mitogen-activated protein kinase 11(MAPK11).Results We revealed that ETV4 was highly expressed in HCC.High levels of ETV4 predicted a poor survival rate of HCC patients.Then we identified ETV4 as a transcription activator of TNF-αand MAPK11.ETV4 was positively correlated with TNF-αand MAPK11 in HCC patients.As expected,an increase in hepatic TNF-αsecretion and macrophage accumulation were observed in the livers of ETV4Hep-TG mice.The protein levels of TNF-α,MAPK11,and CD68 were significantly higher in the livers of ETV4Hep-TG mice compared with wild type mice but lower in ETV4fl/fl,alb-cre mice compared with ETV4fl/fl mice as treated with DEN-CCL4,indicating that ETV4 functioned as a driver of TNF-α/MAPK11 expression and macrophage accumulation during hepatic inflammation.Hepatocyte-specific knockout of ETV4 significantly prevented development of DEN-CCL4-induced HCC,while transgenic expression of ETV4 promoted growth of HCC.Conclusions ETV4 promoted hepatic inflammation and HCC by activating transcription of TNF-αand MAPK11.Both the ETV4/TNF-αand ETV4/MAPK11 axes represented two potential therapeutic targets for highly associated hepatic inflammation and HCC.ETV4+TNF-αwere potential prognostic markers for HCC patients.

Immunogenic molecules associated with gut bacterial cell walls:chemical structures,immune-modulating functions,and mechanisms

Interactions between gut microbiome and host immune system are fundamental to maintaining the intestinal mucosal barrier and homeostasis.At the host-gut microbiome interface,cell wall-derived molecules from gut commensal bacteria have been reported to play a pivotal role in training and remodeling host immune responses.In this article,we review gut bacterial cell wall-derived molecules with characterized chemical structures,including peptidoglycan and lipid-related molecules that impact host health and disease processes via regulating innate and adaptive immunity.Also,we aim to discuss the structures,immune responses,and underlying mechanisms of these immunogenic molecules.Based on current advances,we propose cell wall-derived components as important sources of medicinal agents for the treatment of infection and immune diseases.

刺激响应性聚合物微针系统经皮药物递释

微针经皮递送系统相比于口服、注射给药具有高效、安全、无痛的给药特点,特别是刺激响应性聚合物微针系统生物相容性好,能够依据环境微变化实现时间和空间上的经皮局部和全身智能给药功能,是当前国际前沿研究课题。本文聚焦于近十年来国内外刺激响应性聚合物微针系统的研究工作,着重综述了聚合物微针的发展演变历程、内外环境刺激响应类型及其响应构效机制。此外,详细阐述了微针制备方法、表征方法、微针系统在生物医药递释、组织器官、皮肤医学及医美领域等方面的应用。刺激响应性聚合物微针系统使用方法简便、力学性能可调、药物精准靶向递送,在经皮靶向给药领域有重大研究意义,未来生物活体负载及标准化的产业应用是研究者不断努力和进步的方向。

Anisotropic gapping of topological Weyl rings in the charge-density-wave superconductor In_(x)TaSe_(2)

Topological materials and topological phases have recently become a hot topic in condensed matter physics.In this work,we report an In-intercalated transition-metal dichalcogenide In_(x)TaSe_(2)(named 112 system),a topological nodal-line semimetal in the prep seffiffinffi ce of both charge density wave(CDW)and superconductivity.In the x=0.58 sample,the 2×√3 commensurate CDW(CCDW)and the 2×2 CCDW are observed below 116 and 77 K,respectively.Consistent with theoretical calculations,the spin–orbital coupling gives rise to two twofold-degenerate nodal rings(Weyl rings)connected by drumhead surface states,confirmed by angle-resolved photoemission spectroscopy.Our results suggest that the 2×2 CCDW ordering gaps out one Weyl ring in accordance with the CDW band folding,while the other Weyl ring remains gapless with intact surface states.In addition,superconductivity emerges at 0.91 K,with the upper critical field deviating from the s-wave behavior at low temperature,implying possibly unconventional superconductivity.Therefore,we think this type of the 112 system may possess abundant physical states and offer a platform to investigate the interplay between CDW,nontrivial band topology and superconductivity.

Proteomic identification and functional characterization of MYH9, Hsc70, and DNAJA1 as novel substrates of HDAC6 deacetylase activity

Histone deacetylase 6 （HDAC6）, a predominantly cyto- plasmic protein deacetylase, participates in a wide range of cellular processes through its deacetylase activity. However, the diverse functions of HDAC6 can- not be fully elucidated with its known substrates. In an attempt to explore the substrate diversity of HDAC6, we performed quantitative proteomic analyses to monitor changes in the abundance of protein lysine acetylation in response to HDAC6 deficiency. We identified 107 proteins with elevated acetylation in the liver of HDAC6 knockout mice. Three cytoplasmic proteins, including myosin heavy chain 9 （MYH9）, heat shock cognate pro- tein 70 （HscT0）, and dnaJ homolog subfamily A member 1 （DNAJA1）, were verified to interact with HDAC6. The acetylation levels of these proteins were negatively regulated by HDAC6 both in the mouse liver and in cultured cells. Functional studies reveal that HDAC6- mediated deacetylation modulates the actin-binding ability of MYH9 and the interaction between Hsc70 and DNAJA1. These findings consolidate the notion that HDAC6 serves as a critical regulator of proteinacetylation with the capability of coordinating various cellular functions.

Chromosome-level assembly and analysis of the Thymus genome provide insights into glandular secretory trichome formation and monoterpenoid biosynthesis in thyme

Thyme has medicinal and aromatic value because of its potent antimicrobial and antioxidant properties.However,the absence of a fully sequenced thyme genome limits functional genomic studies of Chinese native thymes.Thymus quinquecostatus Celak.,which contains large amounts of bioactive monoterpenes suchas thymol and carvacrol,is an important wild medicinal and aromatic plant in China.Monoterpenoids are abundant in glandular secretory trichomes.Here,high-fidelity and chromatin conformation capture technologies were used to assemble and annotate the T.quinquecostatus genome at the chromosome level.The 13 chromosomes of T.quinquecostatus had a total length of 528.66 Mb,a contig N50 of 8.06 Mb,and a BUSCO score of 97.34%.We found that T.quinquecostatus had experienced two whole-genome duplications,with the most recent event occurring4.34 million years ago.Deep analyses of the genome,in conjunction with comparative genomic,phylogenetic,transcriptomic,and metabonomic studies,uncovered many regulatory factors and genes related to monoterpenoids and glandular secretory trichome development.Genes encoding terpene synthase(TPS),cytochrome P450 monooxygenases(CYPs),short-chain dehydrogenase/reductase(SDR),R2R3-MYB,and homeodomain-leucine zipper(HD-ZIP)IV were among those present in the T.quinquecostatus genome.Notably,Tq02G002290.1(TqTPS1)was shown to encode the terpene synthase responsible for catalyzing production of the main monoterpene product g-terpinene from geranyl diphosphate(GPP).Our study provides significant insight into the mechanisms of glandular secretory trichome formation and monoterpenoid biosynthesis in thyme.This work will facilitate the development of molecular breeding tools to enhance the production of bioactive secondary metabolites in Lamiaceae.

Influence ofγ-Fe2O3 nanoparticles doping on the image sticking in VAN-LCD

Image sticking in liquid crystal display(LCD)is related to the residual direct current(DC)voltage(RDCV)on the cell and the dynamic response of the liquid crystal materials.According to the capacitance change of the liquid crystal cell under the DC bias,the saturated RDCV(SRDCV)can be obtained.The response time can be obtained by testing the optical dynamic response of the liquid crystal cell,thereby evaluating the image sticking problem.Based on this,the image sticking of vertical aligned nematic(VAN)LCD(VAN-LCD)with different cell thicknesses(3.8μm and 11.5μm)and different concentrations ofγ-Fe2O3 nanoparticles(0.017 wt.%,0.034 wt.%,0.051 wt.%,0.068 wt.%,0.136 wt.%,0.204 wt.%,and 0.272 wt.%)was evaluated,and the effect of nano-doping was analyzed.It is found that the SRDCV and response time decrease firstly and then increase with the increase of the doping concentration ofγ-Fe2O3 nanoparticles in the VAN cell.When the doping concentration is 0.034 wt.%,theγ-Fe2O3 nanoparticles can adsorb most of the free impurity ions in liquid crystal materials,resulting in 70%reduction in the SRDCV,8.11%decrease in the decay time,and 15.49%reduction in the rise time.The results show that the doping ofγ-Fe2O3 nanoparticles can effectively improve the image sticking of VAN-LCD and provide useful guidance for improving the display quality.