Enhanced Precision Therapy of Multiple Myeloma Through Engineered Biomimetic Nanoparticles with Dual Targeting

Multiple myeloma(MM)is the second most prevalent hematological malignancy.Current MM treatment strategies are hampered by systemic toxicity and suboptimal therapeutic efficacy.This study addressed these limitations through the development of a potent MM-targeting chemotherapy strategy,which capitalized on the high binding affinity of alendronate for hydroxyapatite in the bone matrix and the homologous targeting of myeloma cell membranes,termed T-PB@M.The results from our investigations highlight the considerable bone affinity of T-PB@M,both in vitro and in vivo.Additionally,this material demonstrated a capability for drug release triggered by low pH conditions.Moreover,T-PB@M induced the generation of reactive oxygen species and triggered cell apoptosis through the poly(ADP-ribose)polymerase 1(PARP1)-Caspase-3-B-cell lymphoma-2(Bcl-2)pathway in MM cells.Notably,T-PB@M preferentially targeted bone-involved sites,thereby circumventing systemic toxic side effects and leading to prolonged survival of MM orthotopic mice.Therefore,this designed target-MM nanocarrier presents a promising and potentially effective platform for the precise treatment of MM.

Research on the Impact of BYD Group’s Green Innovation on Corporate Financial Performance under the Background of“Dual Carbon”

With the increasingly severe global climate change problem,the“dual carbon”goals(peak carbon emissions and carbon neutrality)have become a common focus of international attention.The report of the 20th National Congress of the Communist Party of China clearly emphasizes the need to accelerate the green transformation of development models,implement comprehensive strategies for frugal development,support the growth of green and low-carbon industries,and promote the concept of green consumption.At the same time,“Made in China 2025”also elaborates on the strategic concept of innovation-driven and green development centered,and strives for breakthroughs in key industries such as new energy vehicles.In such a macro environment,adopting green innovation measures by enterprises not only contributes to ecological protection but also has an undeniable impact on their economic performance and overall value.This article takes BYD Group as a case study to explore in detail the positive effects of green innovation on its economic performance.We first systematically organized and analyzed BYD’s specific practices in green innovation;Then,by examining three key financial indicators,BYD’s current financial situation was analyzed in depth;On this basis,combined with research data,the positive impact of green innovation on BYD’s financial performance was revealed;Finally,based on the analysis results,relevant suggestions are proposed to provide reference for the sustainable development of enterprises in the context of“dual carbon.”

Dual Targeting to Mitochondria and Chloroplasts： Characterization of Thr-tRNA Synthetase Targeting Peptide

There is a group of proteins that are encoded by a single gene, expressed as a single precursor protein and dually targeted to both mitochondria and chloroplasts using an ambiguous targeting peptide. Sequence analysis of 43 dual targeted proteins in comparison with 385 mitochondrial proteins and 567 chloroplast proteins ofArabidopsis thaliana revealed an overall significant increase in phenylalanines, leucines, and serines and a decrease in acidic amino acids and glycine in dual targeting peptides （dTPs）. The N-terminal portion of dTPs has significantly more serines than mTPs. The number of arginines is similar to those in mTPs, but almost twice as high as those in cTPs. We have investigated targeting determinants of the dual targeting peptide of Thr-tRNA synthetase （ThrRS-dTP） studying organellar import of N- and C-terminal deletion constructs of ThrRS-dTP coupled to GFR These results show that the 23 amino acid long N-terminal portion of ThrRS-dTP is crucial but not sufficient for the organellar import. The C-terminal deletions revealed that the shortest peptide that was capable of conferring dual targeting was 60 amino acids long. We have purified the ThrRS- dTP（2-60） to homogeneity after its expression as a fusion construct with GST followed by CNBr cleavage and ion exchange chromatography. The purified ThrRS-dTP（2-60） inhibited import of pF1β into mitochondria and of pSSU into chloroplasts at μM concentrations showing that dual and organelle-specific proteins use the same organellar import pathways. Furthermore, the CD spectra of ThrRS-dTP（2-60） indicated that the peptide has the propensity for forming α-helical structure in membrane mimetic environments; however, the membrane charge was not important for the amount of induced helical structure. This is the first study in which a dual targeting peptide has been purified and investigated by biochemical and biophysical means.

Engineering a folic acid-decorated ultrasmall gemcitabine nanocarrier for breast cancer therapy: Dual targeting of tumor cells and tumor-associated macrophages

Combination of passive targeting with active targeting is a promising approach to improve the therapeutic efficacy of nanotherapy.However,most reported polymeric systems have sizes above100 nm,which limits effective extravasation into tumors that are poorly vascularized and have dense stroma.This will,in turn,limit the overall effectiveness of the subsequent uptake by tumor cells via active targeting.In this study,we combined the passive targeting via ultra-small-sized gemcitabine(GEM)-based nanoparticles(NPs)with the active targeting provided by folic acid(FA)conjugation for enhanced dual targeted delivery to tumor cells and tumor-associated macrophages(TAMs).We developed an FAmodified prodrug carrier based on GEM(PGEM)to load doxorubicin(DOX),for co-delivery of GEM and DOX to tumors.The co-delivery system showed small particle size of~10 nm in diameter.The ligand-free and FA-targeted micelles showed comparable drug loading efficiency and a sustained DOX release profile.The FA-conjugated micelles effectively increased DOX uptake in cultured KB cancer cells that express a high level of folate receptor(FR),but no obvious increase was observed in 4T1.2 breast cancer cells that have a low-level expression of FR.Interestingly,in vivo,systemic delivery of FAPGEM/DOX led to enhanced accumulation of the NPs in tumor and drastic reduction of tumor growth in a murine 4T1.2 breast cancer model.Mechanistic study showed that 4T1.2 tumor grown in mice expressed a significantly higher level of FOLR2,which was selectively expressed on TAMs.Thus,targeting of TAM may also contribute to the improved in vivo targeted delivery and therapeutic efficacy.

Dual Targeting of a Mitochondrial Protein： The Case Study of Cytochrome C1

As a result of the endosymbiotic gene transfer, the majority of proteins of mitochondria and chloroplasts is encoded in the nucleus and synthesized in the cytosol as precursor molecules carrying N-terminal transit peptides for the transport into the respective target organelle. In most instances, transport takes place into either mitochondria or chloroplasts, although a few examples of dual targeting into both organelles have been described. Here, we show by a combination of three different experimental strategies that also cytochrome c1 of potato, a component of the respiratory electron transport chain, is imported not only into mitochondria, but also into plastids. In organello import experiments with isolated mitochondria and chloroplasts, which were analyzed in both single and mixed organelte assays, demonstrate that the processing products accumulating after import within the two endosymbiotic organelles are different in size. Dual targeting of cytochrome c1 is observed also in vivo, after biolistic transformation of leaf epidermal cells with suitable reporter constructions. Finally, Western analyses employing cytochrome c1-specific antiserum provide evidence that the protein accumulates in significant amounts in mitochondria and chloroplasts of both pea and spinach. The possible consequences of our findings on the relevance of the dual targeting phenomenon are discussed.

Import Determinants of Organelle-Specific and Dual Targeting Peptides of Mitochondria and Chloroplasts in Arabidopsis thaliana

Most of the mitochondrial and chloroplastic proteins are synthesized in the cytosol as precursor proteins carrying an N-terminal targeting peptide （TP） directing them specifically to a correct organelle. However, there is a group of proteins that are dually targeted to mitochondria and chloroplasts using an ambiguous N-terminal dual targeting peptide （dTP）. Here, we have investigated pattern properties of import determinants of organelle-specific TPs and dTPs combining mathematical multivariate data analysis （MVDA） with in vitro organellar import studies. We have used large datasets of mitochondrial and chloroplastic proteins found in organellar proteomes as well as manually selected data sets of experimentally confirmed organelle-specific TPs and dTPs from Arabidopsis thaliana. Two classes of organelle-specific TPs could be distinguished by MVDA and potential patterns or periodicity in the amino acid sequence contributing to the separation were revealed, dTPs were found to have intermediate sequence features between the organelle-specific TPs. Interestingly, introducing positively charged residues to the dTPs showed clustering towards the mitochondrial TPs in silico and resulted in inhibition of chloroplast, but not mitochondrial import in in vitro organellar import studies. These findings suggest that positive charges in the N-terminal region of TPs may function as an ＇avoidance signal＇ for the chloroplast import.

Dual Targeting of a Processing Peptidase into Both Endosymbiotic Organelles Mediated by a Transport Signal of Unusual Architecture

As a result of the endosymbiotic gene transfer, the majority of proteins of mitochondria and chloroplasts are encoded in the nucleus and synthesized in the cytosol as precursor proteins carrying N-terminal transport signals for the ＇re-import＇ into the respective target organelle. Most of these transport signals are monospecific, although some of them have dual targeting properties, that is, they are recognized both by mitochondria and by chloroplasts as target organelles. We have identified alpha-MPP2, one of the two isoforms of the substrate binding subunit of mitochondrial processing peptidase of Arabidopsis thaliana, as a novel member of this class of nuclear-encoded organelle proteins. As demonstrated by in organello transport experiments with isolated organelles and by in vivo localization studies employing fluorescent chimeric reporter proteins, the N-terminal region of the alpha-MPP2 precursor comprises transport signals for the import into mitochondria as well as into chloroplasts. Both signals are found within the N-terminal 79 residues of the precursor protein, where they occupy partly separated and partly overlapping regions. Deletion mapping combined with in organello and in vivo protein transport studies demonstrate an unusual architecture of this transport signal, suggesting a composition of three functionally separated domains.

Ecological-Based Mining:A Coal-Water-Thermal Collaborative Paradigm in Ecologically Fragile Areas in Western China

A substantial reduction in groundwater level,exacerbated by coal mining activities,is intensifying water scarcity in western China’s ecologically fragile coal mining areas.China’s national strategic goal of achieving a carbon peak and carbon neutrality has made eco-friendly mining that prioritizes the protection and efficient use of water resources essential.Based on the resource characteristics of mine water and heat hazards,an intensive coal-water-thermal collaborative co-mining paradigm for the duration of the mining process is proposed.An integrated system for the production,supply,and storage of mining companion resources is achieved through technologies such as roof water inrush prevention and control,hydrothermal quality improvement,and deep-injection geological storage.An active preventive and control system achieved by adjusting the mining technology and a passive system centered on multiobjective drainage and grouting treatment are suggested,in accordance with the original geological characteristics and dynamic process of water inrush.By implementing advanced multi-objective drainage,specifically designed to address the“skylight-type”water inrush mode in the Yulin mining area of Shaanxi Province,a substantial reduction of 50%in water drillings and inflow was achieved,leading to stabilized water conditions that effectively ensure subsequent safe coal mining.An integrated-energy complementary model that incorporates the clean production concept of heat utilization is also proposed.The findings indicate a potential saving of 8419 t of standard coal by using water and air heat as an alternative heating source for the Xiaojihan coalmine,resulting in an impressive energy conservation of 50.2%and a notable 24.2%reduction in carbon emissions.The ultra-deep sustained water injection of 100 m^(3)·h^(-1)in a single well would not rupture the formation or cause water leakage,and 7.87×10^(5)t of mine water could be effectively stored in the Liujiagou Formation,presenting a viable method for mine-water management in the Ordos Basin and providing insights for green and low-carbon mining.

Current status of novel biologics and small molecule drugs in the individualized treatment of inflammatory bowel disease

Treatment strategies for inflammatory bowel disease(IBD)are rapidly evolving with the development of biologics and small molecule drugs(SMDs).However,these drugs are not guaranteed to be effective in all patients,and a“ceiling effect”of biologic monotherapy may occur.This issue highlights an unmet need for optimizing the use of biologics and predicting therapeutic responses.Thus,the development of new drugs with novel mechanisms of action is urgently needed for patients with primary nonresponse and secondary loss of response to conventional biologics and SMDs.In addition,combining different biologics or SMDs has been proposed as a novel strategy to enhance treatment efficacy in IBD,which theoretically has multidimensional anti-inflammatory potential.Based on the current evidence available for IBD,dual targeted therapy may be a promising strategy for refractory IBD patients who have failed in multiple biologic treatments or who have extraintestinal manifestation.Additionally,identifying the subgroup of IBD patients who are responding to biological combination therapies is also equally important in stable disease remission.In this review,we summarize the newly developed biologics and SMDs and the current status of biologics/SMDs to highlight the development of individualized treatment in IBD.

Progress, challenge and significance of building a carbon industry system in the context of carbon neutrality strategy

Carbon dioxide storage and utilization has become an inevitable trend and choice for sustainable development under the background of global climate change and carbon neutrality.Carbon industry which is dominated by CO_(2) capture,utilization and storage/CO_(2) capture and storage(CCUS/CCS)is becoming a new strategic industry under the goal of carbon neutrality.The sustainable development of carbon industry needs to learn from the experiences of global oil and gas industry development.There are three types of“carbon”in the earth system.Black carbon is the CO_(2) that has not been sequestered or used and remains in the atmosphere for a long time;grey carbon is the CO_(2) that has been fixed or permanently sequestered in the geological body,and blue carbon is the CO_(2) that could be converted into products for human use through biological,physical,chemical and other ways.The carbon industry system covers carbon generation,carbon capture,carbon transportation,carbon utilization,carbon sequestration,carbon products,carbon finance,and other businesses.It is a revolutionary industrial field to completely eliminate“black carbon”.The development of carbon industry technical system takes carbon emission reduction,zero carbon,negative carbon and carbon economy as the connotation,and the construction of a low-cost and energy-efficient carbon industry system based on CCUS/CCS are strategic measures to achieve the goal of carbon neutrality and clean energy utilization globally.This will promote the“four 80%s”transformation of China's energy supply,namely,to 2060,the percentage of zero-carbon new energy in the energy consumption will be over 80%and the CO_(2) emission will be decreased by 80%to ensure the carbon emission reduction of total 80×10^(8) t from the percentage of carbon-based fossil energy in the energy consumption of over 80%,and the percentage of CO_(2) emission from energy of over 80%in 2021.The carbon industry in China is facing three challenges,large CO_(2) emissions,high percentage of coal in energy consumption,and poor innovative system.Three strategic measures are proposed accordingly,including:(1)unswervingly develop carbon industrial system and ensure the achievement of carbon neutrality as scheduled by 2060;(2)vigorously develop new energy sources and promote a revolutionary transformation of China’s energy production and consumption structure;(3)accelerate the establishment of scientific and technological innovation system of the whole CO_(2) industry.It is of great significance for continuously optimization of ecological environment and construction of green earth and ecological earth to develop the carbon industry system,utilize clean energy,and achieve the strategic goal of global carbon neutrality.

Dual-targeting prodrug nanotheranostics for NIR-Ⅱfluorescence imaging-guided photo-immunotherapy of glioblastoma

Glioblastoma(GBM) therapy is severely impaired by the blood-brain barrier(BBB) and invasive tumor growth in the central nervous system.To improve GBM therapy,we herein presented a dual-targeting nanotheranostic for second near-infrared(NIR-Ⅱ) fluorescence imaging-guided photoimmunotherapy.Firstly,a NIR-Ⅱ fluorophore MRP bearing donor-acceptor-donor(D-A-D) backbone was synthesized.Then,the prodrug nanotheranostics were prepared by self-assembling MRP with a prodrug of JQ1(JPC) and T7 ligand-modified PEG5k-DSPE.T7 can cross the BBB for tumor-targeted delivery of JPC and MRP.JQ1 could be restored from JPC at the tumor site for suppressing interferon gamma-inducible programmed death ligand 1 expression in the tumor cells.MRP could generate NIR-Ⅱ fluorescence to navigate 808 nm laser,induce a photothermal effect to trigger in-situ antigen release at the tumor site,and ultimately elicit antitumor immunogenicity.Photo-immunotherapy with JPC and MRP dual-loaded nanoparticles remarkably inhibited GBM tumor growth in vivo.The dual-targeting nanotheranostic might represent a novel nanoplatform for precise photo-immunotherapy of GBM.

Both metaxin and Tom20 together with two mitochondria-specific motifs support mitochondrial targeting of dual-targeting AtSufE1

Plant cells have two endosymbiotic organelles,chloroplasts,and mitochondria.These organelles perform specific functions that depend on organelle-specific proteins.The majority of chloroplast and mitochondrial proteins are specifically imported by the transit peptide and presequence,respectively.However,a significant number of proteins are also dually targeted to these two organelles.Currently,it is not fully understood how proteins are dually targeted to both chloroplasts and mitochondria.In this study,the mechanism underlying mitochondrial targeting of dual targeting At Suf E1 in Arabidopsis was elucidated.The N-terminal fragment containing 80 residues of AtSufE1(AtSufE1N80)was sufficient to confer dual targeting of reporter protein,At SufE1N80:GFP,in protoplasts.Two sequence motifs,two arginine residues at 15and 21positions,and amino acid(aa)sequence motif AKTLLLRPLK from the 31to 40aa position,were responsible for targeting to mitochondria a portion of reporter proteins amid the chloroplast targeting.The sequence motif PSEVPFRRT from the 41 stto 50 thaa position constitutes a common motif for targeting to both chloroplasts and mitochondria.For mitochondrial import of At Suf E1:N80,Metaxin played a critical role.In addition,Bi FC and protein pull-down experiments showed that At Suf E1N80 specifically interacts with import receptors,Metaxin and Tom20.The interaction of At Suf E1N80 with Metaxin was required for the interaction with Tom20.Based on these results,we propose that mitochondrial targeting of dual-targeting At Suf E1 is mediated by both mitochondria-specific and common sequence motifs in the signal sequence through the interaction with import receptors,Metaxin and Tom20,in a successive manner.

Temperature-sensitive polypeptide brushes-coated mesoporous silica nanoparticles for dual-responsive drug release

A biopolymer-inorganic hybrid system(MSN@PBLGF) is designed and fabricated from mesoporous silica nanoparticles(MSNs) and folic acid(FA)-terminated temperature-sensitive synthetic polypeptide,i.e.,poly(γ-benzyl-L-glutamate)(PBLG) derivative,through a thiol-disulfide exchange reaction,where MSNs with high drug loading capacity serve as drug nanocarriers and the biocompatible PBLG biopolymer brushes installed on MSN surface through disulfide bonds endow the system with tumor-specific recognition ability and GSH/temperature dual-stimuli responsiveness.Controlled drug release experiments indicate that DOX can be tightly hosted in the system with limited premature release,but efficiently released in response to an increased concentration of GSH and/or an elevated temperature.Intracellular experiments demonstrate that the DOX-loaded MSN@PBLGF nanohybrid shows outstanding cellular uptake and cell-growth inhibition effects on human lung cancer cell line A549 in comparison with healthy human cells such as hepatocyte cells LO2.

Research on the Asymmetric Effect of Fixed-Asset Investment on China's Primary Energy Production in the Context of Energy Transformation

Under China’s“Dual Carbon”target(DCT),“clean replacement”on the energy supply side and“electric energy replacement”on the energy consumption side are the ways to achieve energy transformation.However,energy projects have a long construction period,complex technology categories,and investment risks that greatly affect the development of energy transformation.Correctly judging the effect of investment changes on primary energy production is of great practical significance to the realization of the DCT.Based on this,NARDL and TVP-SV-VAR models are innovatively used to reveal the nonlinear effect of fixed-asset investment on China’s primary energy production.The results show that the marginal effect of investment growth on coal production is about 1.44 times that of investment reduction.Similarly,the marginal effect of oil and gas investment growth is about 1.21times that of investment reduction.Due to the influence of resource constraints,China’s traditional fossil energy still has varying degrees of path dependence on the investment-driven development model.For non-fossil energy,investment in hydropower and nuclear power has an inverse correlation with the change in production.Negative marginal efficiency and diseconomies of scale have hindered the development of the hydropower and nuclear power industries.In addition,the asymmetric effect is not yet significant for the short development time and technical constraints of wind and solar power.From the impulse response results,the impact curves of investment in wind and solar power are generally positive,and investment has different degrees of time-delay and time-varying effects on various energy production,which verifies the heterogeneity of investment adjustment mechanisms in different energy industries.

Complement-targeted therapy for autoimmune diseases

The success and safety seen in treating complement-mediated hemolysis conditions has sparked the development of targeted therapies for rare autoimmune diseases,with expansion to more common autoimmune conditions.Various classes of drugs,including small molecules,peptides,monoclonal antibodies,and small interfering RNA(siRNA),are undergoing development to specifically address complement activity.A dual approach targeting both complement and other immune components may be required for autoimmune diseases characterized by inflammation and complex pathogenic mechanisms.siRNA,which suppresses complement production,is emerging as a potent therapeutic tool.Combining a complement-blocking siRNA drug with a treatment that reduces autoantibodies could prove clinically feasible and impactful in managing these conditions.

The Arabidopsis Protein CGLD11 Is Required for Chloroplast ATP Synthase Accumulation

ATP synthases in chloroplasts （cpATPase） and mitochondria （mtATPase） are responsible for ATP production during photosynthesis and oxidative phosphorylation, respectively. Both enzymes consist of two multi- subunit complexes, the membrane-bound coupling factor O and the soluble coupling factor 1. During cpATPase biosynthesis, several accessory factors facilitate subunit production and orchestrate complex assembly. Here, we describe a new auxiliary protein in Arabidopsis thaliana, which is required for cpATPase accumulation. AtCGLD11 （CONSERVED IN THE GREEN LINEAGE AND DIATOMS 11） is a protein without any known functional domain and shows dual localization to chloroplasts and mitochondria. Loss of AtCGLDll function results in reduced levels of cpATPase and impaired photosynthetic performance with lower rates of ATP synthesis. In yeast two-hybrid experiments, AtCGLD11 interacts with the 13 subunits of the cpATPase and mtATPase. Our results suggest that AtCGLD11 functions in F1 assembly during cpATPase biogenesis, while its role in mtATPase biosynthesis may not, or not yet, be essential.

Optimal scheduling of wind-photovoltaic power-generation system based on a copula-based conditional value-at-risk model

Increasing the application of renewable energy in the power system is an effective way to achieve the goal of‘Dual Carbon’.At the same time,the high proportion of renewable energy connected to the grid endangers the safe operation of the power system.To solve this problem,this paper proposes the application of a copula function to describe the correlation between wind power and photovoltaic power,and reduce the uncertainty of power-system operation with a high proportion of renewable energy.In order to increase the robustness of the model,this paper proposes the application of the conditional value-at-risk theory to construct the objective function of the model and effectively control the tail risk of power-system operation costs.Through case analysis,it is found that the model proposed in this paper has strong practicality and economy.