Relaxin-encapsulated polymeric metformin nanoparticles remodel tumor immune microenvironment by reducing CAFs for efficient triple-negative breast cancer immunotherapy

Cancer-associated fibroblasts(CAFs)are one of the most abundant stromal cells in the tumor microenvironment which mediate desmoplastic response and are the primary driver for an immunosuppressive microenvironment,leading to the failure of triple-negative breast cancer(TNBC)immunotherapy.Therefore,depleting CAFs may enhance the effect of immunotherapy(such as PD-L1 antibody).Relaxin(RLN)has been demonstrated to significantly improve transforming growth factor-β(TGF-β)induced CAFs activation and tumor immunosuppressive microenvironment.However,the short half-life and systemic vasodilation of RLN limit its in vivo efficacy.Here,plasmid encoding relaxin(pRLN)to locally express RLN was delivered with a new positively charged polymer named polymeric metformin(PolyMet),which could increase gene transfer efficiency significantly and have low toxicity that have been certified by our lab before.In order to improve the stability of pRLN in vivo,this complex was further formed lipid poly-γ-glutamic acid(PGA)/PolyMetpRLN nanoparticle(LPPR).The particle size of LPPR was 205.5±2.9 nm,and the zeta potential was+55.4±1.6 mV.LPPR displayed excellent tumor penetrating efficacy and weaken proliferation of CAFs in 4T1luc/CAFs tumor spheres in vitro.In vivo,it could reverse aberrantly activated CAFs by decreasing the expression of profibrogenic cytokine and remove the physical barrier to reshape the tumor stromal microenvironment,which enabled a 2.2-fold increase in cytotoxic T cell infiltration within the tumor and a decrease in immunosuppressive cells infiltration.Thus,LPPR was observed retarded tumor growth by itself in the 4T1 tumor bearing-mouse,and the reshaped immune microenvironment further led to facilitate antitumor effect when it combined with PD-L1 antibody(aPD-L1).Altogether,this study presented a novel therapeutic approach against tumor stroma using LPPR to achieve a combination regimen with immune checkpoint blockade therapy against the desmoplastic TNBC model.

The characterization of auditory brainstem response(ABR) waveforms: A study in tree shrews(Tupaia belangeri)

To characterize the patterns of ABR waves in tree shrews, we must understand the hearing sensitivity and auditory function of healthy adult tree shrews. Fifteen tree shrews(30 ears) were stimulated with clicks and tone-pips at 11 different frequencies from 1 to 60 kHz. The ABR waves were recorded and analyzed. The ABR consisted of five to seven positive waves in the first 10 ms after a click stimulus, and the average hearing threshold of component III was 27.86 ± 3.78 dB SPL. Wave III was the largest and most clear. The ABR threshold was related to the tone-pip sitmulus by a "U" shaped curve. The sensitive frequency was approximately 8 kHz in tree shrews. The latencies systematically decreased with increasing stimulus frequencies. The ABR amplitudes of wave III increased as the sound pressure level increased. All of these results provide an empirical basis for future studies of hearing diseases in tree shrews.

Light induces petal color change in Quisqualis indica(Combretaceae)

Petal color change, a common phenomenon in angiosperms, is induced by various environmental and endogenous factors. Interestingly, this phenomenon is important for attracting pollinators and further reproductive success. Quisqualis indica L.(Combretaceae) is a tropical Asian climber that undergoes sequential petal color change from white to pink to red. This color changing process is thought to be a good strategy to attract more pollinators. However, the underlying physiological and biochemical mechanisms driving this petal color change phenomenon is still underexplored. In this context, we investigated whether changes in pH, pollination, light, temperature or ethylene mediate petal color change. We found that the detected changes in petal pH were not significant enough to induce color alterations. Additionally, pollination and temperatures of 20-30℃did not alter the rate of petal color change; however, flowers did not open when exposed to constant temperatures at 15℃ or 35℃.Moreover, the application of ethylene inhibitor, i.e., silver thiosulphate, did not prevent color change. It is worth mentioning here that in our study we found light as a strong factor influencing the whole process of petal color change, as petals remained white under dark conditions. Altogether, the present study suggests that petal color change in Q. indica is induced by light and not by changes in petal pH, pollination, ethylene, or temperature, while extremely low or high temperatures affect flower anthesis. In summary, our findings represent the probable mechanism underlying the phenomenon of petal color change, which is important for understanding flower color evolution.

A drug-loaded composite coating to improve osteogenic and antibacterial properties of Zn-1Mg porous scaffolds as biodegradable bone implants

Zinc(Zn)alloy porous scaffolds produced by additive manufacturing own customizable structures and biodegradable functions,having a great application potential for repairing bone defect.In this work,a hydroxyapatite(HA)/polydopamine(PDA)composite coating was constructed on the surface of Zn-1Mg porous scaffolds fabricated by laser powder bed fusion,and was loaded with a bioactive factor BMP2 and an antibacterial drug vancomycin.The microstructure,degradation behavior,biocompatibility,antibacterial performance and osteogenic activities were systematically investigated.Compared with as-built Zn-1Mg scaffolds,the rapid increase of Zn2+,which resulted to the deteriorated cell viability and osteogenic differentiation,was inhibited due to the physical barrier of the composite coating.In vitro cellular and bacterial assay indicated that the loaded BMP2 and vancomycin considerably enhanced the cytocompatibility and antibacterial performance.Significantly improved osteogenic and antibacterial functions were also observed according to in vivo implantation in the lateral femoral condyle of rats.The design,influence and mechanism of the composite coating were discussed accordingly.It was concluded that the additively manufactured Zn-1Mg porous scaffolds together with the composite coating could modulate biodegradable performance and contribute to effective promotion of bone recovery and antibacterial function.

人民政协协商与基层协商的互通互融——基于淮安市“码”上议事厅的研究

协商民主是实践全过程人民民主的重要形式,推进协商民主广泛多层制度化发展是新时代新发展阶段的重大课题。淮安市政协积极探索政协协商与基层协商衔接的创新模式,坚持以技术赋能推动政协协商与基层协商有效衔接;坚持党建引领,谋求协商民主全方位提升;坚持重心下沉,推动协商体系多层次重塑;创新运行程序,实现协商效能全过程释放;强化保障机制,推进协商格局多角度夯固;通过组织、权责、资源、程序与主体五大要素衔接,保障政协协商与基层协商互通互融。淮安经验表明,用好人民政协优势,发挥人民政协作用,推动政协协商与基层协商有效衔接,有利于促进协商品质的有效提升、协商体系的多层次扩展、协商效能的全过程释放,对加快发展全过程人民民主、提升基层治理现代化水平具有重要意义。

Analysis of thermal characteristics for EMuS capture solenoids

Purpose The Experimental Muon Source(EMuS)project proposed at the China Spallation Neutron Source(CSNS)is a facility for muon applications and neutrino physics research.The EMuS target station adopts a superconducting solenoid scheme to meet the requirements of muon and pion capture.The capture solenoid consists of four solenoids with different apertures to meet the requirements of the central magnetic field up to 5T.Due to the high-irradiation environment,the capture solenoid adopts aluminum-stabilized Rutherford cable winding scheme to reduce the heat deposition on the coil.The magnet design considers the degradation of properties of aluminum stabilizer after continuous neutral irradiation.Due to the characteristics of the coil material,the magnet has different steady-state thermal characteristics and quench performance during different operating periods.Method and result Through the analysis of the operating characteristics,this paper proposes the design of the magnet structure and quench protection scheme.According to the simulation,the current design can satisfy a continous operating time of 200 days per year.

Heterogeneous Catalysts toward CO_(2) Hydrogenation for Sustainable Carbon Cycle

Fossil fuels such as coal,oil,and natural gas have been increasingly consumed and depleted for the use as energy and raw materials,thus compelling the search for the substitutes.Notably,we are unable to produce energy,but only collect what nature gives us.To attain a sustainable development,we should use renewable energy to close the loop of materials,especially for carbon as the origin of life.Among diversified carbon-based chemicals,CO_(2) is the end product of any combustion process,either biological or chemical.