Is it time to rethink the Alzheimer's disease drug development strategy by targeting its silent phase?

Alzheimer＇s disease （AD） is the most frequent cause of dementia in the western world. In clinical terms, AD is characterized by progres- sive cognitive decline that usually begins with memory impairment. As the disease progresses, AD inevitably affects all intellectual functions including executive functions, leading to complete dependence for basic activities of daily life and premature death.

Utilizing engineered extracellular vesicles as delivery vectors in the management of ischemic stroke:a special outlook on mitochondrial delivery

Ischemic stroke is a secondary cause of mortality worldwide,imposing considerable medical and economic burdens on society.Extracellular vesicles,serving as natural nanocarriers for drug delivery,exhibit excellent biocompatibility in vivo and have significant advantages in the management of ischemic stroke.However,the uncertain distribution and rapid clearance of extracellular vesicles impede their delivery efficiency.By utilizing membrane decoration or by encapsulating therapeutic cargo within extracellular vesicles,their delivery efficacy may be greatly improved.Furthermore,previous studies have indicated that microvesicles,a subset of large-sized extracellular vesicles,can transport mitochondria to neighboring cells,thereby aiding in the restoration of mitochondrial function post-ischemic stroke.Small extracellular vesicles have also demonstrated the capability to transfer mitochondrial components,such as proteins or deoxyribonucleic acid,or their sub-components,for extracellular vesicle-based ischemic stroke therapy.In this review,we undertake a comparative analysis of the isolation techniques employed for extracellular vesicles and present an overview of the current dominant extracellular vesicle modification methodologies.Given the complex facets of treating ischemic stroke,we also delineate various extracellular vesicle modification approaches which are suited to different facets of the treatment process.Moreover,given the burgeoning interest in mitochondrial delivery,we delved into the feasibility and existing research findings on the transportation of mitochondrial fractions or intact mitochondria through small extracellular vesicles and microvesicles to offer a fresh perspective on ischemic stroke therapy.

The role of cholesterol metabolism in lung cancer

Elevated serum cholesterol metabolism is associated with a reduced risk of lung cancer.Disrupted cholesterol metabolism is evident in both lung cancer patients and tumor cells.Inhibiting tumor cell cholesterol uptake or biosynthesis pathways,through the modulation of receptors and enzymes such as liver X receptor and sterolregulatory element binding protein 2,effectively restrains lung tumor growth.Similarly,promoting cholesterol excretion yields comparable effects.Cholesterol metabolites,including oxysterols and isoprenoids,play a crucial role in regulating cholesterol metabolism within tumor cells,consequently impacting cancer progression.In lung cancer patients,both the cholesterol levels in the tumor microenvironment and within tumor cells significantly influence cell growth,proliferation,and metastasis.The effects of cholesterol metabolism are further mediated by the reprogramming of immune cells such as T cells,B cells,macrophages,myeloid-derived suppressor cells,among others.Ongoing research is investigating drugs targeting cholesterol metabolism for clinical treatments.Statins,targeting the cholesterol biosynthesis pathway,are widely employed in lung cancer treatment,either as standalone agents or in combination with other drugs.Additionally,drugs focusing on cholesterol transportation have shown promise as effective therapies for lung cancer.In this review,we summarized current research regarding the rule of cholesterol metabolism and therapeutic advances in lung cancer.

Improving cancer therapy by combining cell biological, physical, and molecular targeting strategies

Successful cancer therapy depends on selective killing of tumor cells while sparing normal cells. Selectivity can be achieved through treatment strategies that target tumor cells. A recent report from the Li laboratory （1） describes an elegant strategy to selectively kill tumor cells by combining several targeting strategies based on cell biological, physical, and molecular （genetic） properties of tumor and normal cells that enhances tumor cell killing in vitro and in an in vivo tumor xenograft model. The idea of using a multiplex targeting approach is reminiscent of strategies in which several antibiotics are used to treat bacterial infections while minimizing the chance that rare antibiotic-resistant mutants will arise within a population.

The inositol metabolism pathway as a target for neuroprotective strategies

Neurodegeneration is characterized by the progressive and permanent loss of neurons.Degeneration typically results in a debilitating loss of function in an otherwise healthy person.Neurodegenerative diseases have enormous direct health care costs,with some estimates for diseases.

Molecular neuro-oncology and development of targeted therapeutic strategies for brain tumors

Brain tumors are a diverse group of malignancies that remain refractory to conventional treatment approaches.Molecular neuro-oncologyhas now begun to clarify the transformed phenotype of brain tumors and identify oncogenic pathways that might be amenable to targetedtherapy.Activity of the phosphoinositide 3;kinase(PI3K)/Akt pathway is often upregulated in brain tumors due to excessive stimu-lation by growth factor receptors and Ras.Loss of function of the tumor suppressor gene PTEN also frequently contributesto

Multi-omics integration reveals potential stage-specific druggable targets in T-cell acute lymphoblastic leukemia

T-cell acute lymphoblastic leukemia(T-ALL),a heterogeneous hematological malignancy,is caused by the developmental arrest of normal T-cell progenitors.The development of targeted therapeutic regimens is impeded by poor knowledge of the stage-specific aberrances in this disease.In this study,we performed multi-omics integration analysis,which included mRNA expression,chromatin accessibility,and gene-dependency database analyses,to identify potential stage-specific druggable targets and repositioned drugs for this disease.This multi-omics integration helped identify 29 potential pathological genes for T-ALL.These genes exhibited tissue-specific expression profiles and were enriched in the cell cycle,hematopoietic stem cell differentiation,and the AMPK signaling pathway.Of these,four known druggable targets(CDK6,TUBA1A,TUBB,and TYMS)showed dysregulated and stage-specific expression in malignant T cells and may serve as stage-specific targets in T-ALL.The TUBA1A expression level was higher in the early T cell precursor(ETP)-ALL cells,while TUBB and TYMS were mainly highly expressed in malignant T cells arrested at the CD4 and CD8 double-positive or single-positive stage.CDK6 exhibited a U-shaped expression pattern in malignant T cells along the naıve to maturation stages.Furthermore,mebendazole and gemcitabine,which target TUBA1A and TYMS,respectively,exerted stage-specific inhibitory effects on T-ALL cell lines,indicating their potential stage-specific antileukemic role in T-ALL.Collectively,our findings might aid in identifying potential stage-specific druggable targets and are promising for achieving more precise therapeutic strategies for T-ALL.

LQTTrack:Multi-Object Tracking by Focusing on Low-Quality Targets Association

Multi-object tracking(MOT)has seen rapid improvements in recent years.However,frequent occlusion remains a significant challenge in MOT,as it can cause targets to become smaller or disappear entirely,resulting in lowquality targets,leading to trajectory interruptions and reduced tracking performance.Different from some existing methods,which discarded the low-quality targets or ignored low-quality target attributes.LQTTrack,with a lowquality association strategy(LQA),is proposed to pay more attention to low-quality targets.In the association scheme of LQTTrack,firstly,multi-scale feature fusion of FPN(MSFF-FPN)is utilized to enrich the feature information and assist in subsequent data association.Secondly,the normalized Wasserstein distance(NWD)is integrated to replace the original Inter over Union(IoU),thus overcoming the limitations of the traditional IoUbased methods that are sensitive to low-quality targets with small sizes and enhancing the robustness of low-quality target tracking.Moreover,the third association stage is proposed to improve the matching between the current frame’s low-quality targets and previously interrupted trajectories from earlier frames to reduce the problem of track fragmentation or error tracking,thereby increasing the association success rate and improving overall multi-object tracking performance.Extensive experimental results demonstrate the competitive performance of LQTTrack on benchmark datasets(MOT17,MOT20,and DanceTrack).

Nanomedicine for acute respiratory distress syndrome: The latest application, targeting strategy, and rational design

Acute respiratory distress syndrome(ARDS)is characterized by the severe inflammation and destruction of the lung aireblood barrier,leading to irreversible and substantial respiratory function damage.Patients with coronavirus disease 2019(COVID-19)have been encountered with a high risk of ARDS,underscoring the urgency for exploiting effective therapy.However,proper medications for ARDS are still lacking due to poor pharmacokinetics,non-specific side effects,inability to surmount pulmonary barrier,and inadequate management of heterogeneity.The increased lung permeability in the pathological environment of ARDS may contribute to nanoparticle-mediated passive targeting delivery.Nanomedicine has demonstrated unique advantages in solving the dilemma of ARDS drug therapy,which can address the shortcomings and limitations of traditional anti-inflammatory or antioxidant drug treatment.Through passive,active,or physicochemical targeting,nanocarriers can interact with lung epithelium/endothelium and inflammatory cells to reverse abnormal changes and restore homeostasis of the pulmonary environment,thereby showing good therapeutic activity and reduced toxicity.This article reviews the latest applications of nanomedicine in pre-clinical ARDS therapy,highlights the strategies for targeted treatment of lung inflammation,presents the innovative drug delivery systems,and provides inspiration for strengthening the therapeutic effect of nanomedicine-based treatment.

System Recovery-Aware Virus Propagation Model and Its Steady-State Analysis

Network structures and human behaviors are considered as two important factors in virus defense currently. However, due to ignorance of network security, normal users usually take simple activities, such as reinstalling computer system, or using the computer recovery system to clear virus. How system recovery influences virus spreading is not taken into consideration currently. In this paper, a new virus propagation model considering the system recovery is proposed first, and then in its steady-state analysis, the virus propagation steady time and steady states are deduced. Experiment results show that models considering system recovery can effectively restrain virus propagation. Furthermore, algorithm with system recovery in BA scale-free network is proposed. Simulation result turns out that target immunization strategy with system recovery works better than traditional ones in BA network.

New Thought about the Marketing Orientation of Middle and Small-sized Enterprises of China

The reasonable marketing orientation is related to the survival and the development of the enterprises. According to the disadvantages and superiority of the middle and small sized enterprises of our country, this paper analyzes the new thought about the marketing orientation from the aspects of marketing product orientation, marketing way orientation, marketing target orientation, marketing strategy orientation and marketing idea orientation. It has great theoretical and practical significance.

“Yin-Yang philosophy”for the design of anticancer drug delivery nanoparticles

Understanding the in vivo transport process provides guidelines for designing ideal nanoparticles(NPs)with higher efficacy and fewer off-target effects.Many factors,such as particle size,morphology,surface potential,structural stability,and etc.,may influence the delivering process of NPs due to the existence of various physiological barriers within the body.Herein,we summarise the distinct influences of NP physicochemical properties on the four consecutive in vivo transport steps:(1)navigating with bloodstream within blood vessels,(2)transport across vasculature walls into tumour tissues,(3)intratumoural transport through the interstitial space,and(4)cellular uptake&intracellular delivery by cancerous cells.We found that the philosophy behind the current consensus for NP design has certain similarities to the“Yin-Yang”theory in traditional Chinese culture.Almost all physicochemical properties,regardless of big or small sizes,long or short length,positive or negative zeta potentials,are double-edged swords.The balance of potential benefits and side effects,drug selectivity and accessibility should be fully considered when optimising particle design,similar to the“Yin-Yang harmony”.This paper presents a comprehensive review of the advancements in NPs research,focusing on their distinct features in tumour targeting,drug delivery,and cell uptake.Additionally,it deliberates on future developmental trends and potential obstacles,thereby aiming to uncover the ways these characteristics influence the NPs’biological activity and provide theoretical guidance for the targeted delivery of NPs.

Recent advances in drug delivery systems for targeting cancer stem cells

Cancer stem cells(CSCs)are a subpopulation of cancer cells with functions similar to those of normal stem cells.Although few in number,they are capable of self-renewal,unlimited proliferation,and multi-directional differentiation potential.In addition,CSCs have the ability to escape immune surveillance.Thus,they play an important role in the occurrence and development of tumors,and they are closely related to tumor invasion,metastasis,drug resistance,and recurrence after treatment.Therefore,specific targeting of CSCs may improve the efficiency of cancer therapy.A series of corresponding promising therapeutic strategies based on CSC targeting,such as the targeting of CSC niche,CSC signaling pathways,and CSC mitochondria,are currently under development.Given the rapid progression in this field and nanotechnology,drug delivery systems(DDSs)for CSC targeting are increasingly being developed.In this review,we summarize the advances in CSC-targeted DDSs.Furthermore,we highlight the latest developmental trends through the main line of CSC occurrence and development process;some considerations about the rationale,advantages,and limitations of different DDSs for CSCtargeted therapies were discussed.

Rational distribution of Ru nanodots on 2D Ti_(3−x)C_(2)T_(y)/g-C_(3)N_(4)heterostructures for boosted photocatalytic H_(2)evolution

Incorporating metal nanodots(NDs)into heterostructures for high charge separation and transfer capacities is one of the most effective strategies for improving their photocatalytic activities.However,controlling the space distribution of metal NDs for optimizing charge transport pathways remains a significant challenge,particularly in two-dimensional(2D)face-to-face heterostructures.Herein,we develop a simple targeted self-reduction strategy for selectively loading Ru NDs onto the Ti_(3−x)C_(2)T_(y)(TC)surface of 2D TC/g-C_(3)N_(4)(CN)heterojunction based on the reductive Ti vacancy defects creatively increased during the preparation of TC/CN by reducing calcination.Notably,the optimized Ru/TC/CN photocatalyst exhibits an outstanding H_(2)evolution rate of 3.21 mmol·g^(−1)·h^(−1)and a high apparent quantum efficiency of 30.9%at 380 nm,which is contributed by the unidirectional transfer of the photogenerated electrons from CN to Ru active sites(CN→TC→Ru)and the suppressed backflow of electrons from Ru sites to CN,as revealed by comprehensive characterizations and density functional theory(DFT)calculations.This work provides a novel strategy for synthesizing the highly efficient photocatalysts with a controllable charge transfer paths,which will boost the development of photocatalysis.

Aggregation-induced emission luminogens for in vivo molecular imaging and theranostics in cancer

Cancer is one of the most fatal diseases for decades.Aggregation-induced emission luminogens(AIEgens)have been recently used as molecular imaging or therapeutic agents in cancers,due to the advantages of large Stokes shift,high quantum yield,great biocompatibility,and strong photostability.AIEgens can specifically target different types of cancer via diverse targeting strategies.AIEgen-based fluorescence imaging,especially near-infrared imaging,demonstrated deep penetration and suitable signal-to-noise ratio,which allows reliable in vivo cancer imaging.Combined with other imaging modalities,AIEgen-based multimodal imaging could provide multidimensional cancer hallmarks from different perspectives.In addition,AIEgenbased phototherapy can be used for photodynamic therapy and photothermal therapy,which facilitate ablation of cancer cells with good biosafety and high therapeutic effects in vivo.AIEgens nanoparticles fabricated with some specific chemicals,drugs,or siRNA,could display synergistic therapeutic effects for cancers.This paper comprehensively describes the current status and future perspectives of AIEgens,which have showed a great potential for the future preclinical and clinical translation on in vivo molecular imaging and theranostics in cancer.