Transferrin-guided intelligent nanovesicles augment the targetability and potency of clinical PLK1 inhibitor to acute myeloid leukemia

Acute myeloid leukemia(AML)remains a most lethal hematological malignancy,partly because of its slow development of targeted therapies compared with other cancers.PLK1 inhibitor,volasertib(Vol),is among the few molecular targeted drugs granted breakthrough therapy status for AML;however,its fast clearance and dose-limiting toxicity greatly restrain its clinical benefits.Here,we report that transferrin-guided polymersomes(TPs)markedly augment the targetability,potency and safety of Vol to AML.Vol-loaded TPs(TPVol)with 4%trans-ferrin exhibited best cellular uptake,effective down-regulation of p-PLK1,p-PTEN and p-AKT and superior apoptotic activity to free Vol in MV-4-11 leukemic cells.Intravenous injection of TPVol gave 6-fold higher AUC than free Vol and notable accumulation in AML-residing bone marrow.The efficacy studies in orthotopic MV-4-11 leukemic model demonstrated that TPVol significantly reduced leukemic cell proportions in periphery blood,bone marrow,liver and spleen,effectively enhanced mouse survival rate,and impeded bone loss.This transferrin-guided nano-delivery of molecular targeted drugs appears to be an interesting strategy towards the development of novel treatments for AML.

Lipid metabolism analysis in esophageal cancer and associated drug discovery

Esophageal cancer is an upper gastrointestinal malignancy with a bleak prognosis.It is still being explored in depth due to its complex molecular mechanisms of occurrence and development.Lipids play a crucial role in cells by participating in energy supply,biofilm formation,and signal transduction processes,and lipid metabolic reprogramming also constitutes a significant characteristic of malignant tumors.More and more studies have found esophageal cancer has obvious lipid metabolism abnormalities throughout its beginning,progress,and treatment resistance.The inhibition of tumor growth and the enhancement of antitumor therapy efficacy can be achieved through the regulation of lipid metabolism.Therefore,we reviewed and analyzed the research results and latest findings for lipid metabolism and associated analysis techniques in esophageal cancer,and comprehensively proved the value of lipid metabolic reprogramming in the evolution and treatment resistance of esophageal cancer,as well as its significance in exploring potential therapeutic targets and biomarkers.

Mitophagy in intracerebral hemorrhage:a new target for therapeutic intervention

Intracerebral hemorrhage is a life-threatening condition with a high fatality rate and severe sequelae.However,there is currently no treatment available for intracerebral hemorrhage,unlike for other stroke subtypes.Recent studies have indicated that mitochondrial dysfunction and mitophagy likely relate to the pathophysiology of intracerebral hemorrhage.Mitophagy,or selective autophagy of mitochondria,is an essential pathway to preserve mitochondrial homeostasis by clearing up damaged mitochondria.Mitophagy markedly contributes to the reduction of secondary brain injury caused by mitochondrial dysfunction after intracerebral hemorrhage.This review provides an overview of the mitochondrial dysfunction that occurs after intracerebral hemorrhage and the underlying mechanisms regarding how mitophagy regulates it,and discusses the new direction of therapeutic strategies targeting mitophagy for intracerebral hemorrhage,aiming to determine the close connection between mitophagy and intracerebral hemorrhage and identify new therapies to modulate mitophagy after intracerebral hemorrhage.In conclusion,although only a small number of drugs modulating mitophagy in intracerebral hemorrhage have been found thus far,most of which are in the preclinical stage and require further investigation,mitophagy is still a very valid and promising therapeutic target for intracerebral hemorrhage in the long run.

High-speed penetration of ogive-nose projectiles into thick concrete targets:Tests and a projectile nose evolution model

The majority of the projectiles used in the hypersonic penetration study are solid flat-nosed cylindrical projectiles with a diameter of less than 20 mm.This study aims to fill the gap in the experimental and analytical study of the evolution of the nose shape of larger hollow projectiles under hypersonic penetration.In the hypersonic penetration test,eight ogive-nose AerMet100 steel projectiles with a diameter of 40 mm were launched to hit concrete targets with impact velocities that ranged from 1351 to 1877 m/s.Severe erosion of the projectiles was observed during high-speed penetration of heterogeneous targets,and apparent localized mushrooming occurred in the front nose of recovered projectiles.By examining the damage to projectiles,a linear relationship was found between the relative length reduction rate and the initial kinetic energy of projectiles in different penetration tests.Furthermore,microscopic analysis revealed the forming mechanism of the localized mushrooming phenomenon for eroding penetration,i.e.,material spall erosion abrasion mechanism,material flow and redistribution abrasion mechanism and localized radial upsetting deformation mechanism.Finally,a model of highspeed penetration that included erosion was established on the basis of a model of the evolution of the projectile nose that considers radial upsetting;the model was validated by test data from the literature and the present study.Depending upon the impact velocity,v0,the projectile nose may behave as undistorted,radially distorted or hemispherical.Due to the effects of abrasion of the projectile and enhancement of radial upsetting on the duration and amplitude of the secondary rising segment in the pulse shape of projectile deceleration,the predicted DOP had an upper limit.

Advantages of nanocarriers for basic research in the field of traumatic brain injury

A major challenge for the efficient treatment of traumatic brain injury is the need for therapeutic molecules to cross the blood-brain barrier to enter and accumulate in brain tissue.To overcome this problem,researchers have begun to focus on nanocarriers and other brain-targeting drug delivery systems.In this review,we summarize the epidemiology,basic pathophysiology,current clinical treatment,the establishment of models,and the evaluation indicators that are commonly used for traumatic brain injury.We also report the current status of traumatic brain injury when treated with nanocarriers such as liposomes and vesicles.Nanocarriers can overcome a variety of key biological barriers,improve drug bioavailability,increase intracellular penetration and retention time,achieve drug enrichment,control drug release,and achieve brain-targeting drug delivery.However,the application of nanocarriers remains in the basic research stage and has yet to be fully translated to the clinic.

Precision targeting in hepatocellular carcinoma:Exploring ligandreceptor mediated nanotherapy

Hepatocellular carcinoma(HCC)is the most common primary liver cancer and poses a major challenge to global health due to its high morbidity and mortality.Conventional chemotherapy is usually targeted to patients with intermediate to advanced stages,but it is often ineffective and suffers from problems such as multidrug resistance,rapid drug clearance,nonspecific targeting,high side effects,and low drug accumulation in tumor cells.In response to these limitations,recent advances in nanoparticle-mediated targeted drug delivery technologies have emerged as breakthrough approaches for the treatment of HCC.This review focuses on recent advances in nanoparticle-based targeted drug delivery systems,with special attention to various receptors overexpressed on HCC cells.These receptors are key to enhancing the specificity and efficacy of nanoparticle delivery and represent a new paradigm for actively targeting and combating HCC.We comprehensively summarize the current understanding of these receptors,their role in nanoparticle targeting,and the impact of such targeted therapies on HCC.By gaining a deeper understanding of the receptor-mediated mechanisms of these innovative therapies,more effective and precise treatment of HCC can be achieved.

Real-time Rescue Target Detection Based on UAV Imagery for Flood Emergency Response

Timely acquisition of rescue target information is critical for emergency response after a flood disaster.Unmanned Aerial Vehicles(UAVs)equipped with remote sensing capabilities offer distinct advantages,including high-resolution imagery and exceptional mobility,making them well suited for monitoring flood extent and identifying rescue targets during floods.However,there are some challenges in interpreting rescue information in real time from flood images captured by UAVs,such as the complexity of the scenarios of UAV images,the lack of flood rescue target detection datasets and the limited real-time processing capabilities of the airborne on-board platform.Thus,we propose a real-time rescue target detection method for UAVs that is capable of efficiently delineating flood extent and identifying rescue targets(i.e.,pedestrians and vehicles trapped by floods).The proposed method achieves real-time rescue information extraction for UAV platforms by lightweight processing and fusion of flood extent extraction model and target detection model.The flood inundation range is extracted by the proposed method in real time and detects targets such as people and vehicles to be rescued based on this layer.Our experimental results demonstrate that the Intersection over Union(IoU)for flood water extraction reaches an impressive 80%,and the IoU for real-time flood water extraction stands at a commendable 76.4%.The information on flood stricken targets extracted by this method in real time can be used for flood emergency rescue.

Enhancement strategies of targetability, response and photostability for in vivo bioimaging

Analyses of the physiology and pathology of active biochemical species in their native contexts are critical for early diagnosis and therapy. Optical imaging has emerged as one of the promising modalities for noninvasive and real-time visualization of important biomolecules or biological events, and it has witnessed major advances in the field of imaging in vitro and in vivo. In this review, we present a survey of common approaches and tactics for enhanced targetability, response rate, and photostability in bioimaging applications. Recently developed and representative examples are illustrated on the cellular and tissue levels.

阿帕替尼治疗腺样囊性癌肺转移1例

腺样囊性癌(adenoid cystic carcinoma,ACC)是一种较少见的来源于腺体的恶性肿瘤,约占头颈部恶性肿瘤的1%[1]。其病程进展缓慢但极易侵袭,有较高的复发率和远处转移率,最常见的转移部位是肺[2]。对于ACC肺转移患者,目前并无特效药物。MYB基因表达失调是ACC患者最常见的突变。

Target acquisition performance in the presence of JPEG image compression

This paper presents an investigation on the effect of JPEG compression on the similarity between the target image and the background,where the similarity is further used to determine the degree of clutter in the image.Four new clutter metrics based on image quality assessment are introduced,among which the Haar wavelet-based perceptual similarity index,known as HaarPSI,provides the best target acquisition prediction results.It is shown that the similarity between the target and the background at the boundary between visually lossless and visually lossy compression does not change significantly compared to the case when an uncompressed image is used.In future work,through subjective tests,it is necessary to check whether this presence of compression at the threshold of just noticeable differences will affect the human target acquisition performance.Similarity values are compared with the results of subjective tests of the well-known target Search_2 database,where the degree of agreement between objective and subjective scores,measured through linear correlation,reached a value of 90%.

Distinct molecular targets of ProEGCG from EGCG and superior inhibition of angiogenesis signaling pathways for treatment of endometriosis

Endometriosis is a common chronic gynecological disease with endometrial cell implantation outside the uterus.Angiogenesis is a major pathophysiology in endometriosis.Our previous studies have demonstrated that the prodrug of epigallocatechin gallate(ProEGCG)exhibits superior anti-endometriotic and anti-angiogenic effects compared to epigallocatechin gallate(EGCG).However,their direct binding targets and underlying mechanisms for the differential effects remain unknown.In this study,we demonstrated that oral ProEGCG can be effective in preventing and treating endometriosis.Additionally,1D and 2D Proteome Integral Solubility Alteration assay-based chemical proteomics identified metadherin(MTDH)and PX domain containing serine/threonine kinase-like(PXK)as novel binding targets of EGCG and ProEGCG,respectively.Computational simulation and BioLayer interferometry were used to confirm their binding affinity.Our results showed that MTDH-EGCG inhibited protein kinase B(Akt)-mediated angiogenesis,while PXK-ProEGCG inhibited epidermal growth factor(EGF)-mediated angiogenesis via the EGF/hypoxia-inducible factor(HIF-1a)/vascular endothelial growth factor(VEGF)pathway.In vitro and in vivo knockdown assays and microvascular network imaging further confirmed the involvement of these signaling pathways.Moreover,our study demonstrated that ProEGCG has superior therapeutic effects than EGCG by targeting distinct signal transduction pathways and may act as a novel antiangiogenic therapy for endometriosis.

Target Detection Algorithm in Foggy Scenes Based on Dual Subnets

Under the influence of air humidity,dust,aerosols,etc.,in real scenes,haze presents an uneven state.In this way,the image quality and contrast will decrease.In this case,It is difficult to detect the target in the image by the universal detection network.Thus,a dual subnet based on multi-task collaborative training(DSMCT)is proposed in this paper.Firstly,in the training phase,the Gated Context Aggregation Network(GCANet)is used as the supervisory network of YOLOX to promote the extraction of clean information in foggy scenes.In the test phase,only the YOLOX branch needs to be activated to ensure the detection speed of the model.Secondly,the deformable convolution module is used to improve GCANet to enhance the model’s ability to capture details of non-homogeneous fog.Finally,the Coordinate Attention mechanism is introduced into the Vision Transformer and the backbone network of YOLOX is redesigned.In this way,the feature extraction ability of the network for deep-level information can be enhanced.The experimental results on artificial fog data set FOG_VOC and real fog data set RTTS show that the map value of DSMCT reached 86.56%and 62.39%,respectively,which was 2.27%and 4.41%higher than the current most advanced detection model.The DSMCT network has high practicality and effectiveness for target detection in real foggy scenes.

The functions of exosomes targeting astrocytes and astrocyte-derived exosomes targeting other cell types

Astrocytes are the most abundant glial cells in the central nervous system;they participate in crucial biological processes,maintain brain structure,and regulate nervous system function.Exosomes are cell-derived extracellular vesicles containing various bioactive molecules including proteins,peptides,nucleotides,and lipids secreted from their cellular sources.Increasing evidence shows that exosomes participate in a communication network in the nervous system,in which astrocyte-derived exosomes play important roles.In this review,we have summarized the effects of exosomes targeting astrocytes and the astrocyte-derived exosomes targeting other cell types in the central nervous system.We also discuss the potential research directions of the exosome-based communication network in the nervous system.The exosome-based intercellular communication focused on astrocytes is of great significance to the biological and/or pathological processes in different conditions in the brain.New strategies may be developed for the diagnosis and treatment of neurological disorders by focusing on astrocytes as the central cells and utilizing exosomes as communication mediators.

Electromagnetic pulses produced by a picosecond laser interacting with solid targets

A high-power laser ablating solid targets induces giant electromagnetic pulses(EMPs),which are intimately pertinent to laser parameters,such as energy and pulse width.In this study,we reveal the features of EMPs generated from a picosecond(ps)laser irradiating solid targets at the SG-Ⅱpicosecond petawatt(PSPW)laser facility.The laser energy and pulse,as well as target material and thickness,show determinative effects on the EMPs’amplitude.More intense EMPs are detected behind targets compared to those at the other three positions,and the EMP amplitude decreases from 90.09 kV/m to 17.8 kV/m with the gold target thickness increasing from 10μm to 20μm,which is suppressed when the laser pulse width is enlarged.The results are expected to provide more insight into EMPs produced by ps lasers coupling with targets and lay the foundation for an effective EMP shielding design in high-power laser infrastructures.

A proteomic landscape of pharmacologic perturbations for functional relevance

Pharmacological perturbation studies based on protein-level signatures are fundamental for drug discovery. In the present study, we used a mass spectrometry (MS)-based proteomic platform to profile the whole proteome of the breast cancer MCF7 cell line under stress induced by 78 bioactive compounds. The integrated analysis of perturbed signal abundance revealed the connectivity between phenotypic behaviors and molecular features in cancer cells. Our data showed functional relevance in exploring the novel pharmacological activity of phenolic xanthohumol, as well as the noncanonical targets of clinically approved tamoxifen, lovastatin, and their derivatives. Furthermore, the rational design of synergistic inhibition using a combination of histone methyltransferase and topoisomerase was identified based on their complementary drug fingerprints. This study provides rich resources for the proteomic landscape of drug responses for precision therapeutic medicine.

Dynamic regulation of the irrigation-nitrogen-biochar nexus for the synergy of yield,quality,carbon emission and resource use efficiency in tomato

Integrated water and fertilizer management is important for promoting sustainable development of facility agriculture,and biochar plays an important role in guaranteeing food production,as well as alleviating water shortages and the overuse of fertilizers.The field experiment had twelve treatments and a control(CK)trial including two irrigation amounts(I1,100%ETm;I2,60%ETm;where ETm is the maximum evapotranspiration),two nitrogen applications(N1,360 kg ha^(−1);N2,120 kg ha^(−1))and three biochar application levels(B1,60 t ha^(−1);B_(2),30 t ha^(−1)and B3,0 t ha^(−1)).A multi-objective synergistic irrigation-nitrogen-biochar application system for improving tomato yield,quality,water and nitrogen use efficiency,and greenhouse emissions was developed by integrating the techniques of experimentation and optimization.First,a coupled irrigation-nitrogen-biochar plot experiment was arranged.Then,tomato yield and fruit quality parameters were determined experimentally to establish the response relationships between irrigation-nitrogen-biochar dosage and yield,comprehensive quality of tomatoes(TCQ),irrigation water use efficiency(IWUE),partial factor productivity of nitrogen(PFPN),and net greenhouse gas emissions(NGE).Finally,a multi-objective dynamic optimization regulation model of irrigation-nitrogen-biochar resource allocation at different growth stages of tomato was constructed which was solved by the fuzzy programming method.The results showed that the application of irrigation and nitrogen to biochar promoted increase in yield,IWUE and PFPN,while it had an inhibitory effect on NGE.In addition,the optimal allocation amounts of water and fertilizer were different under different scenarios.The yield of the S1 scenario increased by 8.31%compared to the B_(1)I_(1)N_(2) treatment;TCQ of the S2 scenario increased by 5.14%compared to the B_(2)I_(2)N_(1) treatment;IWUE of the S3 scenario increased by 10.01%compared to the B1I2N2 treatment;PFPN of the S4 scenario increased by 9.35%compared to the B_(1)I_(1)N_(2) treatment;and NGE of the S5 scenario decreased by 11.23%compared to the B_(2)I1N1 treatment.The optimization model showed that the coordination of multiple objectives considering yield,TCQ,IWUE,PFPN,and NGE increased on average from 4.44 to 69.02%compared to each treatment when the irrigation-nitrogen-biochar dosage was 205.18 mm,186 kg ha^(−1)and 43.31 t ha^(−1),respectively.This study provides a guiding basis for the sustainable management of water and fertilizer in greenhouse tomato production under drip irrigation fertilization conditions.

Treat to target in Crohn’s disease:A practical guide for clinicians

A treat-to-target(T2T)approach applies the principles of early intervention and tight disease control to optimise long-term outcomes in Crohn's disease.The Selecting Therapeutic Targets in Inflammatory Bowel Disease(STRIDE)-II guidelines specify short,intermediate,and long-term treatment goals,documenting specific treatment targets to be achieved at each of these timepoints.Scheduled appraisal of Crohn’s disease activity against pre-defined treatment targets at these timepoints remains central to determining whether current therapy should be continued or modified.Consensus treatment targets in Crohn’s disease comprise combination clinical and patient-reported outcome remission,in conjunction with biomarker normalisation and endoscopic healing.Although the STRIDE-II guidelines endorse the pursuit of endoscopic healing,clinicians must consider that this may not always be appropriate,acceptable,or achievable in all patients.This underscores the need to engage patients at the outset in an effort to personalise care and individualise treatment targets.The use of non-invasive biomarkers such as faecal calprotectin in conjunction with cross-sectional imaging techniques,particularly intestinal ultrasound,holds great promise;as do emerging treatment targets such as transmural healing.Two randomised clinical trials,namely,CALM and STARDUST,have evaluated the efficacy of a T2T approach in achieving endoscopic endpoints in patients with Crohn’s disease.Findings from these studies reflect that patient subgroups and Crohn’s disease characteristics likely to benefit most from a T2T approach,remain to be clarified.Moreover,outside of clinical trials,data pertaining to the real-world effectiveness of a T2T approach remains scare,highlighting the need for pragmatic real-world studies.Despite the obvious promise of a T2T approach,a lack of guidance to support its integration into real-world clinical practice has the potential to limit its uptake.This highlights the need to describe strategies,processes,and models of care capable of supporting the integration and execution of a T2T approach in real-world clinical practice.Hence,this review seeks to examine the current and emerging literature to provide clinicians with practical guidance on how to incorporate the principles of T2T into routine clinical practice for the management of Crohn’s disease.

Sexual dimorphism of G protein-coupled receptor signaling in the brain

G protein-coupled receptors(GPCRs)represent the most substantial family of membrane receptors that are targeted by U.S.Food and Drug Administration-approved drugs.Much of the preclinical research to understand the pharmacology of many membrane receptors including GPCRs is derived from studies in male animal models(Karp and Reavey,2019).

Classification and technical target of water electrolysis for hydrogen production

Continuous efforts are underway to reduce carbon emissions worldwide in response to global climate change.Water electrolysis technology,in conjunction with renewable energy,is considered the most feasible hydrogen production technology based on the viable possibility of large-scale hydrogen production and the zero-carbon-emission nature of the process.However,for hydrogen produced via water electrolysis systems to be utilized in various fields in practice,the unit cost of hydrogen production must be reduced to$1/kg H_(2).To achieve this unit cost,technical targets for water electrolysis have been suggested regarding components in the system.In this paper,the types of water electrolysis systems and the limitations of water electrolysis system components are explained.We suggest guideline with recent trend for achieving this technical target and insights for the potential utilization of water electrolysis technology.

Complement-dependent neuroinflammation in spinal cord injury:from pathology to therapeutic implications

Spinal cord injury remains a major cause of disability in young adults,and beyond acute decompression and rehabilitation,there are no pharmacological treatments to limit the progression of injury and optimize recovery in this population.Following the thorough investigation of the complement system in triggering and propagating cerebral neuroinflammation,a similar role for complement in spinal neuroinflammation is a focus of ongoing research.In this work,we survey the current literature investigating the role of complement in spinal cord injury including the sources of complement proteins,triggers of complement activation,and role of effector functions in the pathology.We study relevant data demonstrating the different triggers of complement activation after spinal cord injury including direct binding to cellular debris,and or activation via antibody binding to damage-associated molecular patterns.Several effector functions of complement have been implicated in spinal cord injury,and we critically evaluate recent studies on the dual role of complement anaphylatoxins in spinal cord injury while emphasizing the lack of pathophysiological understanding of the role of opsonins in spinal cord injury.Following this pathophysiological review,we systematically review the different translational approaches used in preclinical models of spinal cord injury and discuss the challenges for future translation into human subjects.This review emphasizes the need for future studies to dissect the roles of different complement pathways in the pathology of spinal cord injury,to evaluate the phases of involvement of opsonins and anaphylatoxins,and to study the role of complement in white matter degeneration and regeneration using translational strategies to supplement genetic models.