Precise Targeting Research Articles

Intraprocedural Three-Dimensional Imaging Registration Optimizes Magnetic Resonance Imaging–Guided Focused Ultrasound and Facilitates Novel Applications

BACKGROUND AND OBJECTIVE: Transcranial magnetic resonance–guided focused ultrasound (MRgFUS) has revolutionized ablative treatment of essential tremor in recent years. However, limitations in precision targeting may account for suboptimal efficacy and significant side effects. We describe a simple intraprocedural three-dimensional image-guided lesion shaping technique that can improve overall outcomes of MRgFUS for essential tremor and facilitate expansion to novel indications. METHODS: A retrospective review of 84 consecutive MRgFUS procedures performed at Pennsylvania Hospital was performed. Comparison of patient demographics, treatment parameters, and clinical outcomes before and after implementation of this protocol was conducted. Further application of this technique in pallidotomy treatments and ablative disconnection of hypothalamic hamartoma are described. RESULTS: After implementation, the median of total number of sonications (7 vs 9, P = .001), number of therapeutic sonications (3 vs 4, P < .0001), and interval time between the first and last sonication (46:10 vs 68:53 minutes, P = .0004) were significantly reduced. Patients expressed greater satisfaction of treatment (94.1% vs 82.4%, P = .018), greater global impression of change (CGI) (7 vs 6, P = .033), and reduced median number of side effects at 6 months (0 vs 1, P = .026). We also successfully implemented this protocol for novel indications. CONCLUSION: Intraprocedural lesion shaping for MRgFUS is a simple and versatile imaging protocol augmentation that improves ablation precision and can improve treatment efficacy and broader neurological application.

Synthetic Biology-Enabled Engineering of Probiotics for Precision and Targeted Therapeutic Delivery Applications

Probiotics, defined as live microorganisms that offer health benefits when consumed in adequate amounts, have traditionally been used to maintain gastrointestinal (GI) health. They are effective in managing conditions such as inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), and antibiotic-associated diarrhea. Recent research, however, has expanded their potential applications beyond the GI tract to include immune modulation, metabolic regulation, and mental health support. Despite these advances, conventional probiotics face limitations such as instability in harsh environments, lack of precise targeting, and ineffective control over drug release. This review explores the application of synthetic biology in addressing these limitations, emphasizing how tools such as CRISPR-Cas systems, synthetic gene circuits, and plasmid-based mechanisms enhance the stability, functionality, and specificity of engineered probiotics for therapeutic delivery. Applications of synthetic biology-enabled probiotics are examined across a range of health contexts, including GI health, cancer therapy, metabolic disorders, immune modulation, and mental well-being. Synthetic biology tools provide precise genetic modifications that improve the stability, viability, and functionality of engineered probiotics, enabling more targeted therapeutic delivery. Additionally, technologies such as encapsulation support probiotic survival, while gene circuits allow programmable, stimulus-responsive therapeutic release. As synthetic biology continues to advance, the development of programmable probiotics holds promise for personalized, targeted medicine, positioning probiotics as living therapeutics and patient-friendly alternatives to conventional therapeutic delivery systems.

MiR-101-3p suppresses proliferation of orbital fibroblasts by targeting pentraxin-3 in thyroid eye disease

Background Excessive proliferation of orbital fibroblasts (OFs) is an essential factor in the pathogenesis of thyroid eye disease (TED). While existing evidence indicates that various microRNAs (miRNAs) significantly contribute to TED development, the precise function and targets of miR-101-3p in TED pathogenesis remain unknown. This research aims to elucidate the effects of miR-101-3p on TED-OFs and identify its potential targets. Methods Orbital adipose tissues were harvested from both TED patients and healthy controls to culture their fibroblasts. MiR-101-3p mimic or mimic negative control (mimic NC) was transfected into OFs from TED patients, with untreated OFs serving as an additional blank control group. Cell proliferation was assessed using cell counting kit-8 (CCK-8) assay, Ki-67 immunofluorescence staining, and the EdU assay, while apoptosis was evaluated via flow cytometry. Quantitative real-time polymerase chain reaction (qRT-PCR) was employed to measure the expression levels of miR-101-3p and pentraxin-3 (PTX3), and PTX3 protein levels were quantified using western blot. A dual-luciferase assay was conducted to ascertain how miR-101-3p and PTX3 interacted. Results The results demonstrated a significant downregulation of miR-101-3p in fibroblasts and TED orbital adipose tissues. Transfection with the miR-101-3p mimic upregulated miR-101-3p levels, significantly reducing OFs proliferation without affecting apoptosis. Overexpression of miR-101-3p led to the downregulation of PTX3 in OFs. The dual-luciferase assay validated miR-101-3p binding to PTX3’s 3’UTR, thereby repressing its expression. Moreover, overexpression of PTX3 partially rescued the miR-101-3p mimic’s inhibitory effect on TED-OFs proliferation. Conclusion Our findings illustrate miR-101-3p’s role in targeting PTX3 to regulate TED-OFs proliferation, providing novel insights into the pathological mechanisms underlying TED development.

Highly sensitive detection of MMP-2 using an electrochemiluminescent biosensor enhanced by ladder-branch hybridization chain reaction.

Anadvanced electrochemiluminescence (ECL) biosensor was developedthat integrates T7 RNA polymerase amplification, ladder-branch hybridization chain reaction (HCR), and the precise targeting capabilities of CRISPR/Cas13a technology. The novelty of this research lies in the unique combination of these three cutting-edge technologies, which has not been previously utilized together in biosensing platforms, enabling highly sensitive and specific detection of biomolecules with exceptional precision. This innovative biosensor addresses the critical need for sensitive and specific detection of matrix metalloproteinase-2 (MMP-2), a key biomarker in cancer diagnostics. Through meticulous optimization of amplification and reaction conditions, the biosensor demonstrated remarkable sensitivity and specificity, achieving a detection limit as low as 6.34 aM, surpassing existing methodologies. The biosensor also exhibited excellent stability and reproducibility across multiple scans and maintained consistent functionality over an extended period, highlighting its reliability for practical applications. The effectiveness of the biosensor was validated using real samples, demonstrating its capability to accurately quantify MMP-2 in complex biological matrices with high recovery and minimal interference. The integration of isothermal amplification and CRISPR/Cas13a within the ECL biosensor platform represents a significant advancement in molecular diagnostics, offering a powerful tool for real-time monitoring of MMP-2. This combination of technologies sets the platform apart from traditional methods, marking a significant step forward in biosensor innovation. This biosensor holds substantial promise for revolutionizing cancer diagnostics and facilitating personalized treatment strategies, ultimately aiming to improve patient outcomes in cancer care. Future research may explore further enhancements and applications of this biosensor in various clinical settings.

Green guardians: Harnessing biopesticides for sustainable vegetable pest management

Insect pests pose significant challenges to vegetable crops, causing not only economic losses but also compromising the quality of our food. Shockingly, up to 20 % of globally produced goods fall victim to these insidious invaders. While chemical insecticides have historically bolstered food production, they come with notable drawbacks, including handling risks, residue concerns and negative impacts on non-target species and the environment.Though they have not yet completely replaced chemical insecticides, biopesticides are becoming key in reducing pesticide overuse and promoting safer, residue-free food and environments. Derived from plants and microorganisms, biopesticides offer a safer alternative, ranging from plant extracts to microbial agents such as bacteria, fungi, viruses and nematodes. Additionally, insect hormones and semiochemicals, along with silica-based mineral products like activated clay and rice husk, contribute to eco-friendly pest control solutions. Cutting-edge nano biopesticides also deliver unparalleled pest control with precision targeting and excellent environmental credentials.In this comprehensive exploration, we delve deep into the myriad forms of biopesticides, their commercial availability, modes of action and the advantages and disadvantages in vegetable pest management. Crucially, we illuminate the path toward integrating biopesticides into holistic pest management strategies, which can lead to healthier crops, increased yields and more sustainable agricultural practices. By emphasizing biopesticides, we can promote environmental safety and support a greener future in agriculture.

NIMG-26. GLIOBLASTOMA TISSUE INVASION MAPPING WITH NOVEL HYPOXIA-TARGETED BLOOD OXYGENATION-LEVEL DEPENDENT MRI

Abstract BACKGROUND Glioblastoma is a devastating incurable malignant primary brain tumor exhibiting an erratic growth pattern and brain tissue invasion exceeding the typically depicted contrast-enhancing lesion on MRI. This behaviour is strongly associated with the presence of aberrant vasculature. Advanced clinical neuroimaging techniques, however, have not provided convincing imaging markers to determine glioblastoma tissue infiltration and monitor treatment effects. We investigated a new imaging technique based on blood oxygenation-level dependent (BOLD) MRI contrast with precise hypoxic respiratory targeting in order to better determine tumor tissue invasion not restricted to the typically depicted focal glioblastoma lesion on contrast-enhanced MRI. METHODS A computer-controlled gas blender was used to induce transient and standardized hypoxic stimulus in isocapnic conditions during echo-planar-imaging acquisition in patients with brain tumors.8,9 Data were preprocessed using SPM and in-house written MATLAB scripts. The induced BOLD signal changes were used to calculate %BOLD signal change during hypoxic stimulus with respect to the baseline, contrast to noise (CNR) ratio and goodness-of-fit (Rsquared) for each voxel in the whole-brain and automatically segmented region of interest (contrast-enhancement, necrosis, edema) and overlayed using color-maps onto anatomical high resolution T1. RESULTS Hypoxic targeting during gas modulation could be performed with high reproducibility, caused no discomfort in patients with brain tumors and was able to induce strong signal change during hypoxic stimulus with high contrast-noise ratio and Rsquared. In particular, when compared with other tumors, BOLD hypoxia glioblastoma tissue invasion maps show very distinct hypoxic signal responses in some cases extending beyond the focal -contrast-enhancing- glioblastoma lesion. CONCLUSION The ability to map at voxel level BOLD hypoxia signal patterns may determine a novel therapeutic imaging marker based on structural vascular alterations in the tumour tissue infiltration zone before these become appreciable with standard neuroimaging. This may support a refinement and tailoring of tumor resection and improve follow-up after resection and during treatment i.e. chemoradiotherapy.

DDEL-02. PRECLINICAL EFFICACY OF IL13RΑ2-TARGETING POLYPEPTIDE-DRUG CONJUGATE (SELF-DEPOTTM ONCOPDC) IN GLIOBLASTOMA AND DIFFUSE INTRINSIC PONTINE GLIOMA

Abstract Glioblastoma (GBM) and diffuse intrinsic pontine glioma (DIPG) are currently incurable cancers. Systemic chemotherapy shows limited efficacy because of the intact blood-brain barrier. Convection-enhanced delivery (CED) offers promise by concentrating high doses of chemotherapeutics directly within these tumors. However, drugs administered via CED often face challenges in confirming precise target delivery and are quickly cleared by increased interstitial fluid flow and drug efflux transporters. This highlights the urgent need for innovative drugs that demonstrate target specificity and prolonged retention capabilities. Intrinsically disordered polypeptides (IDPs), derived from tropoelastin, self-assemble into water-insoluble structures with extended retention properties triggered by body temperature. IL13Rα2, differentially amplified in U87MG GBM and SF8628 DIPG cells, serves as a target for therapeutic intervention. An IL13Rα2-targeting IDP (XM161) was developed by incorporating IL13Rα2 binding sequences into the IDP domains. XM161 demonstrated high selectivity in binding to IL13Rα2, with Kd values of 1,786 nM for IL13Rα1 and 12.8 nM for IL13Rα2. Conjugation of XM161 with SN38, a potent topoisomerase I inhibitor, resulted in XM161-SN38, which remained in a dissolved state up to 50°C but formed insoluble aggregates above 27°C in the presence of cerebrospinal fluid. XM161-SN38 exhibited strong cytotoxicity against U87MG and SF8628 cells, with IC50 values of 14.2 nM and 0.48 nM, respectively. Importantly, XM161-SN38 demonstrated efficacy in overcoming Temozolomide resistance in T98G GBM cells, with IC50 values of 3.35 nM compared to 10.87 nM for unconjugated SN38. In orthotopic xenograft models established in BALB/cSlc-nu/nu male mice using U87MG-Luc2 cells, three doses (3 x 0.95 μg SN38 equivalents) of XM161-SN38 delivered via CED were well tolerated and significantly extended median survival to over 65 days, providing a notable survival benefit compared to untreated controls (42 days) and Topotecan-treated group (42.5 days). These findings validate the feasibility and therapeutic potential of XM161-SN38 for GBM treatment. Ongoing studies are underway to investigate the safety and pharmacokinetics of XM161-SN38 in tumor-naive mouse brains.

DDEL-09. AS1411 APTAMER-CONJUGATED NANOSPHERES FOR TARGETING GLIOBLASTOMA THERAPY

Abstract Postoperative chemotherapy remains essential for treating glioblastoma (GBM), with nanocarrier-based drug delivery emerging as the most efficient method. However, non-specific delivery across the blood-brain barrier (BBB) can limit drug accumulation in tumors and cause damage to nearby tissues. As cancer progresses, angiogenic processes lead to the formation of an irregular blood-tumor barrier (BTB), necessitating nanodrug platforms for precise targeting and efficient drug delivery to cancer cells. In this study, we aimed to demonstrate targeted cancer therapy by selectively identifying tumor cells overexpressing nucleolin (NCL) protein using Dox-loaded AS1411 aptamer-conjugated nanospheres. Drug nanocarriers were synthesized from small molecules with sizes ranging from 100 to 300 nm to facilitate drug delivery. Selective drug delivery and cellular uptake were demonstrated for NCL-positive GBM cells (U87 and U251) compared to NCL-negative normal human astrocyte (NHA) cells. Flow cytometric analysis using FAM dye-labeled AS1411 aptamer-conjugated nanospheres confirmed that drug delivery to GBM U87 and U251 cells was actively targeted by specific AS1411-NCL interactions. Confocal laser scanning microscopy and cytotoxicity analysis confirmed that inoculation of Dox-loaded AS1411 aptamer-conjugated nanospheres induced selective internalization in GBM U87 and U251 cells. Moreover, to evaluate cytotoxicity and anti-tumor effects after treatment with PBS, Apt-Nanospheres, Free Dox, and Dox-Apt-Nanospheres, the results were analyzed through cell counting kit (CCK-8) analysis, evaluation of differences in 3D tumor sphere radii, and an in vivo GBM xenograft tumor model. The AS1411 aptamer-conjugated nanosphere drug delivery system was developed for dual-target treatment of GBM. AS1411-mediated specific recognition and drug accumulation significantly enhanced binding to NCL-positive U87 and U251 cells and improved cytotoxicity efficiency compared to Free Dox. Additionally, this study demonstrated that the active targeting model using aptamer-mediated drug delivery was more effective in improving drug penetration and retention in tumor cells than non-specific enhanced permeability and retention (EPR)-mediated delivery and passive drug delivery.

Precision Cancer Therapy Enabled Anti-Epidermal Growth Factor Receptor-Conjugated Manganese Core Phthalocyanine Bismuth Nanocomposite for Dual Imaging-Guided Breast Cancer Treatment.

Cancer remains a formidable global health challenge, demanding the exploration of innovative treatment modalities with minimized side effects. One promising avenue involves the synergistic integration of targeted photothermal/photodynamic therapy (PTT/PDT), utilizing specially designed functional nanomaterials for precise cancer diagnosis and treatment. This study introduces a composite biomaterial, anti-epidermal growth factor receptor-conjugated manganese core phthalocyanine bismuth (anti-EGFR-MPB), synthesized for precise cancer imaging and treatment. The biomaterial, synthesized via a solvothermal process, effectively treats and images breast cancer in mouse models. Its biomimetic design targets cancer cells precisely, with dual imaging for real-time monitoring. The biomimetic design of the composite enables precise targeting of cancer cells, whereas the dual imaging allows for real-time visualization and monitoring of the treatment. Invivo examinations confirm substantial damage to tumor tissues with no recurrence following 808-nm laser irradiation. The composite shows strong fluorescence/photoacoustic imaging (PAI) contrast, aiding malignancy detection. Biological assays and histological analyses confirmed the efficacy of the nanocomposite in inducing apoptosis in cancer cells. The integrated targeted dual image-guided phototherapy offered by this composite substantially enhances the precision and efficacy of cancer therapy, achieving an impressive photothermal efficiency of ~33.8%. Our findings demonstrate the utility of the anti-EGFR-MPB nanocomposite for both invitro and invivo photoacoustic image-guided PTT and PDT. The optimal treatment strategy for triple-negative breast cancer is found to be the use of 250 μg/ml of nanocomposite irradiated with 1.0 W/cm2 808-nm laser for 7 min.

Unveiling tomorrow: Carbonic anhydrase activators and inhibitors pioneering new frontiers in Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disorder and a principal basis of dementia in the elderly population globally. Recently, human carbonic anhydrases (hCAs, EC 4.2.1.1) were demonstrated as possible new targets for treating AD. hCAs are vital for maintaining pH balance and performing other physiological processes as they catalyze the reversible hydration of carbon dioxide to bicarbonate and a proton. Current research indicates that hCA plays a role in brain functions critical for transmitting neural signals. Activation of carbonic anhydrase (CA) has emerged as a promising avenue in addressing memory loss and cognitive issues. Conversely, the exploration of CA inhibition represents a novel frontier in this field. By enhancing glial fitness and cerebrovascular health and blocking amyloid-β (Aβ)-induced mitochondrial dysfunction pathways, cytochrome C (CytC) release, caspase 9 activation, and H2O2 generation in neurons, CA inhibitors improve cognition and lessen the pathology caused by Aβ. Recent research has pushed hCAs into the spotlight as critical players in AD pathogenesis and precise therapeutic targets. The captivating dilemma of choosing between hCA inhibitors and activators looms large, as inhibitors reduce Aβ aggregation and improve cerebral blood flow, while activators enhance cerebrovascular functions and restore pH balance. The current review sheds light on the clinical evidence for hCAs and the roles of inhibitors and activators in AD. Additionally, this review offers a fascinating outlook on the data that may aid medicinal chemists in designing and developing new leads that are more effective and selective for upcoming in vitro and in vivo studies, allowing for the discovery and introduction of novel drug candidates for the treatment of AD to the market and into the clinical pipeline.

Nanoparticles in Subunit Vaccines: Immunological Foundations, Categories, and Applications.

Subunit vaccines, significant in next-generation vaccine development, offer precise targeting of immune responses by focusing on specific antigens. However, this precision often comes at the cost of eliciting strong and durable immunity, posing a great challenge to vaccine design. To address this limitation, recent advancements in nanoparticles (NPs) are utilized to enhance antigen delivery efficiency and boost vaccine efficacy. This review examines how the physicochemical properties of NPs influence various stages of the immune response during vaccine delivery and analyzes how different NP types contribute to immune activation and enhance vaccine performance. It then explores the unique characteristics and immune activation mechanisms of these NPs, along with their recent advancements, and highlights their application in subunit vaccines targeting infectious diseases and cancer. Finally, it discusses the challenges in NP-based vaccine development and proposes future directions for innovation in this promising field.

Optimizing Solid Rocket Missile Trajectories: A Hybrid Approach Using an Evolutionary Algorithm and Machine Learning

This paper introduces a novel approach for modeling and optimizing the trajectory and behavior of small solid rocket missiles. The proposed framework integrates a six-degree-of-freedom (6DoF) simulation environment experimentally tuned for accuracy, with a combination of genetic algorithms (GAs) and machine learning (ML) to enhance the performance of the missile path. In the initial phase, a GA is employed to optimize the missile’s trajectory for efficient target acquisition, defining key launch parameters such as the ramp angle and lateral maneuver force to minimize positional errors and to ensure effective target engagement. Following trajectory optimization, the derived data are used to train an ML model that predicts setup parameters, significantly reducing computational costs and time. This close integration enables real-time adjustments for acquiring moving targets, thereby improving accuracy and minimizing maneuvering costs. This study also explores the application of fluidic thrust vectoring for small rockets, providing an innovative solution to enhance maneuverability and control, especially at low speeds. The proposed framework was validated using experimental launch data from the Icarus Team. The methodology offers a robust and cost-effective solution for precision targeting and improved maneuverability in aerospace and defense contexts.

A Cross-talk between Nanomedicines and Cardiac Complications: Comprehensive View.

Cardiovascular Diseases (CVDs) are the leading cause of global morbidity and mortality, necessitating innovative approaches for both therapeutics and diagnostics. Nanoscience has emerged as a promising frontier in addressing the complexities of CVDs. This study aims to explorethe interaction of CVDs and Nanomedicine (NMs), focusing on applications in therapeutics and diagnostics. In the realm of therapeutics, nanosized drug delivery systems exhibit unique advantages, such as enhanced drug bioavailability, targeted delivery, and controlled release. NMs platform, including liposomes, nanoparticles, and carriers, allows the precise drug targeting to the affected cardiovascular tissues with minimum adverse effects and maximum therapeutic efficacy. Moreover, nanomaterial (NM) enables the integration of multifunctional components, such as therapeutic agents and target ligands, into a single system for comprehensive CVD management. Diagnostic fronts of NMs offer innovative solutions for early detection and monitoring of CVDs. Nanoparticles and nanosensors enable highly sensitive and specific detection of Cardiac biomarkers, providing valuable insights into a disease state, its progression, therapeutic outputs, etc. Further, nano-based technology via imaging modalities offers high high-resolution imaging, aiding in the vascularization of cardiovascular structures and abnormalities. Nanotechnology-based imaging modalities offer high-resolution imaging and aid in the visualization of cardiovascular structures and abnormalities. The cross-talk of CVDs and NMs holds tremendous potential for revolutionizing cardiovascular healthcare by providing targeted and efficient therapeutic interventions, as well as sensitive and early detection for the improvement of patient health if integrated with Artificial Intelligence (AI).

Ultrasound‐Responsive Lipid Nanoparticles for Targeted Therapy and Controlled Drug Release in Non‐Small Cell Lung Cancer

AbstractMultifunctional drug delivery systems offer tremendous potential for improving antitumor efficacy, precise drug targeting, and controlled drug release in treating non‐small cell lung cancer (NSCLC). In this study, the study develops a novel tumor‐targeting ultrasound‐responsive lipid nanoparticle (TUSL) platform capable of responding to external stimulation, enabling precise drug delivery with controlled release at the tumor site while minimizing systemic exposure and side effects. The TUSL platform is designed to carry doxorubicin (DOX) and tetrandrine (TET), specifically for drug‐resistant NSCLC. The developed TUSL exhibits a nano sized spherical structure with a hydrodynamic size of 141.8 nm, accommodating anti‐cancer drugs with loading capacities of 3.8% and 6.2% for TET and DOX, respectively. TUSL is engineered to target the epidermal growth factor receptor (EGFR) while demonstrating an ultrasound‐triggered drug release profile. Through the generation of CO2 bubbles upon ultrasound stimulation, the TUSL enhances DOX and TET internalization into tumor cells. In tumor‐bearing mice, TUSL administration demonstrates a superior tumor accumulation with minimal off‐target toxicity. The combined treatment with DOX and TET within TUSL exhibits synergistic effects, effectively inhibiting the growth of drug‐resistant NSCLC tumors. These findings highlight the efficacy of the EGFR‐targeted TUSL formulation in overcoming drug resistance and enhancing therapeutic outcomes in NSCLC.

CD38 as theranostic target in oncology.

CD38 is a multifunctional transmembrane glycoprotein found in multiple tissues and overexpressed in many cancer cells, notably in hematological malignancies such as leukemia and multiple myeloma (MM). Therefore, targeting CD38 remains an attractive strategy for cancer treatment in hematological malignancies as well as in solid tumors. It plays a critical role in the progression of these diseases through its ADP-ribosyl cyclase and cADPR-hydrolase activities. Its importance has led to the development of various anti-CD38 monoclonal antibodies (mAbs), including daratumumab and isatuximab, approved for MM treatment. These mAbs exert their anti-tumor effects through Fc-dependent immune mechanisms and immunomodulation, enhancing T-cell and NK-cell-mediated responses. However, resistance mechanisms arise during the treatment with daratumumab, creating the necessity for new therapies. This review explains current knowledge about the role of CD38 as a target in oncology and aims to delineate the use of single domain antibodies (sdAbs) as innovative theranostic tools in nuclear medicine. For diagnostic purposes, PET radionuclides like 68Ga, 64Cu, and SPECT radionuclides like 99mTc and 111In, are commonly used. Significant progress has been made in anti-CD38 radioligand therapy (RLT), with anti-CD38 antibodies providing insights into tumor biology and treatment efficacy. In terms of therapy, RLT is a promising approach that offers precise targeting of malignant cells while minimizing exposure to healthy tissue. This involves the use of radionuclides emitting α particles, like 225Ac, 212Pb or 211At, and β--particles like 90Y, 131I, or 177Lu, to exert cytotoxic effects. Derived from Camelidae heavy chain antibodies, sdAbs offer advantages over conventional mAbs such as small size, high stability, specificity, and ability to recognize hidden epitopes. CD38-specific sdAbs, such as sdAb 2F8, characterized by our laboratory, showing excellent tumor targeting and their engineered constructs, such as biparatopic antibodies and chimeric antibodies, represent a new generation of theranostic agents for diagnosis and treatment CD38-expressing malignancies.

Exploring structural and biological insights of TEAD through rational design and synthesis of niflumic acid derivatives

Transcriptional enhanced associate domain (TEAD) transcription factors undergo auto-palmitoylation, which is critical to mediate their function and maintain stability. Targeting the palmitate binding pocket of TEAD holds considerable promise for drug discovery, and it can be characterised into three components: a conserved cysteine, a hydrophobic main pocket, and a hydrophilic side pocket. Endogenous palmitate and several known TEAD inhibitors interact with the cysteine and hydrophobic residues in the deep hydrophobic pocket. We anticipate that precise targeting of the polar side pocket could facilitate the discovery of inhibitors with enhanced potencies and properties. Herein, we selected niflumic acid as the core scaffold suitable for targeting the three characteristic components of TEAD palmitate pocket. Reversible and irreversible compounds with substituents capable of directing each part of the palmitate pocket were designed. The newly synthesised compounds inhibited the palmitoylation and transcriptional activity of TEAD and elicited growth-inhibitory effects against several carcinomas, including mesothelioma.

Piecewise Time Polynomials-Based Control Methods for Obstacle Avoidance and Precision Positioning of Tower Crane Systems with Varying Cable Lengths

During the hoisting and lowering operations of a tower crane, dynamic variations in cable lengths significantly influence the oscillation frequency and amplitude of the load. These variations complicate the oscillation characteristics, heightening the challenge of balancing obstacle avoidance with precise positioning. To tackle this issue, we propose a trajectory planning and tracking control method that integrates hoisting control to reduce the impact of varying cable lengths on load swinging and achieve accurate positioning during obstacle navigation. A novel definition of swing angle is introduced to model the crane’s rigid and swinging components separately, enhancing model accuracy while simplifying complexity. A piecewise polynomial constructs the load trajectory in a low-dimensional flat space, which is then mapped to a high-dimensional generalized state space through a homeomorphic transformation, ensuring trajectory smoothness and traceability. A fractional-order sliding mode controller is employed to facilitate rapid and precise tracking of the actuated degrees of freedom, suppressing load oscillation while maintaining positioning accuracy. Experimental validation on a tower crane platform shows that the proposed strategy enables smooth obstacle avoidance and precise target point reaching, even with varying cable lengths.

Modulating versatile pathways using a cleavable PEG shell and EGFR-targeted nanoparticles to deliver CRISPR-Cas9 and docetaxel for triple-negative breast cancer inhibition.

Human antigen R (HuR), an RNA-binding protein, is implicated in regulating mRNA stability and translation in cancer, especially in triple-negative breast cancer (TNBC), a highly aggressive form. CRISPR/Cas9-mediated HuR knockout (HuR CRISPR) presents a promising genetic therapeutic approach, but it encounters transfection limitations. Docetaxel (DTX), an effective cytotoxic agent against metastatic breast cancer (BC), faces challenges related to vehicle-associated adverse events in DTX formulations. Therefore, we designed multifunctional nanoparticles with pH-sensitive PEG derivatives and targeting peptides to enable efficient HuR CRISPR and DTX delivery to human TNBC MDA-MB-231 cells and tumor-bearing mice. Our findings indicated that these nanoparticles displayed pH-responsive cytotoxicity, precise EGFR targeting, efficient tumor penetration, successful endosomal escape, and accurate nuclear and cytoplasmic localization. They also demonstrated the ability to spare normal cells and prevent hemolysis. Our study concurrently modulated multiple pathways, including EGFR, Wnt/β-catenin, MDR, and EMT, through the regulation of EGFR/PI3K/AKT, HuR/galectin-3/GSK-3β/β-catenin, and P-gp/MRPs/BCRP, as well as YAP1/TGF-β/ZEB1/Slug/MMPs. The combined treatment arrested the cell cycle at the G2 phase and inhibited EMT, effectively impeding tumor progression. Tissue distribution, biochemical assays, and histological staining revealed the enhanced safety profile of pH-responsive PEG- and peptide-modified nanoformulations in TNBC mice. The DTX-embedded and peptide-modified nanoparticles mitigated the side effects of DTX, enhanced cytotoxicity in TNBC MDA-MB-231 cells, and exhibited remarkable antitumor efficacy and safety in TNBC-bearing mice with HuR CRISPR deletion. Collectively, the combination therapy of DTX and CRISPR/Cas9 offers an effective platform for delivering antineoplastic agents and gene-editing systems to combat tumor resistance and progression in TNBC.

An intelligence enhancement method for USV navigation visual measurement based on variable gradient soft-threshold correction

Maritime image enhancement is crucial in marine engineering for applications like unmanned surface vessels (USV) visual measurement and path planning. This paper proposes an image enhancement algorithm based on variable gradient soft-threshold correction (VGSC), tailored for USV intelligent navigation. By calculating the gradient of the two-dimensional difference quotient function of the pixels, we determine the pixel distribution and threshold. An innovative dynamic equalization function is applied to compress maximum pixel values and stretch minimum ones, allowing for adaptive adjustment of the threshold. The results indicate that the VGSC algorithm effectively suppresses background noise, thereby facilitating the extraction of target contour pixel information. When evaluated using four image assessment indicators, the VGSC algorithm enhances the image quality by 20.09 % and 28.92 % compared to bilateral filtering and Gamma correction, respectively. This method excels in enhancing image details and suppressing noise, promising robust application in multi-modal data fusion and precise maritime target detection.

Prioritizing conservation sites for multi-pond systems to maintain protection of water quality in a fragmented agricultural catchment

Precise targeting of conservation practices to the most effective sites in multi-pond systems (MPS) is critical for resource optimization and water quality improvement. Previous studies generally prioritized ponds for conservation practices considering nutrient removal efficiency. However, they have frequently overlooked the role of ponds in sediment interception and the impact of human activities and environmental factors around the pond. Herein, the present study developed and applied a novel framework for pond prioritization by integrating the Pressure-State-Response (PSR) model, graph theory, and K-mean clustering. The framework consists of three components. An indicator system is developed to represent the nutrient removal performance of any MPS, impacts on catchment sediment connectivity, external threats, and human-initiated conservation. A flow path network considering natural and artificial elements was constructed to calculate indicator values. A cluster analysis was conducted on the index values of different ponds, and a hierarchical sorting method were used to prioritize ponds. The framework was applied to the Guilinqiao Catchment, a typical fragmented agricultural catchment in the Yangtze River Basin, China. The study has quantified the Pressure, State, and Response indices of different ponds in this catchment, prioritized the ponds, and drawn recommendations for conserving MPSs based on field surveys and remote sensing data. Ponds with higher Pressure index, higher State index, and lower Response index scores should be targeted as conservation priorities. This framework provides an effective method for ensuring management of MPSs to sustainably maximize water cleanup capacity with limited resources.