Histone chaperone CAF-1 promotes HIV-1 latency by leading the formation of phase-separated suppressive nuclear bodies.

HIV-1 latency is a major obstacle to achieving a functional cure for AIDS. Reactivation of HIV-1-infected cells followed by their elimination via immune surveillance is one proposed strategy for eradicating the viral reservoir. However, current latency-reversing agents (LRAs) show high toxicity and low efficiency, and new targets are needed to develop more promising LRAs. Here, we found that the histone chaperone CAF-1 (chromatin assembly factor 1) is enriched on the HIV-1 long terminal repeat (LTR) and forms nuclear bodies with liquid-liquid phase separation (LLPS) properties. CAF-1 recruits epigenetic modifiers and histone chaperones to the nuclear bodies to establish and maintain HIV-1 latency in different latency models and primary CD4+ T cells. Three disordered regions of the CHAF1A subunit are important for phase-separated CAF-1 nuclear body formation and play a key role in maintaining HIV-1 latency. Disruption of phase-separated CAF-1 bodies could be a potential strategy to reactivate latent HIV-1.

ORC1 enhances repressive epigenetic modifications on HIV-1 LTR to promote HIV-1 latency.

The human immunodeficiency virus type 1 (HIV-1) reservoir consists of latently infected cells which present a major obstacle to achieving a functional cure for HIV-1. The formation and maintenance of HIV-1 latency have been extensively studied, and latency-reversing agents (LRAs) that can reactivate latent HIV-1 by targeting the involved host factors are developed; however, their clinical efficacies remain unsatisfactory. Therefore, it is imperative to identify novel targets for more potential candidates or better combinations for LRAs. In this study, we utilized CRISPR affinity purification in situ of regulatory elements system to screen for host factors associated with the HIV-1 long terminal repeat region that could potentially be involved in HIV-1 latency. We successfully identified that origin recognition complex 1 (ORC1), the largest subunit of the origin recognition complex, contributes to HIV-1 latency in addition to its function in DNA replication initiation. Notably, ORC1 is enriched on the HIV-1 promoter and recruits a series of repressive epigenetic elements, including DNMT1 and HDAC1/2, and histone modifiers, such as H3K9me3 and H3K27me3, thereby facilitating the establishment and maintenance of HIV-1 latency. Moreover, the reactivation of latent HIV-1 through ORC1 depletion has been confirmed across various latency cell models and primary CD4+ T cells from people living with HIV-1. Additionally, we comprehensively validated the properties of liquid-liquid phase separation (LLPS) of ORC1 from multiple perspectives and identified the key regions that promote the formation of LLPS. This property is important for the recruitment of ORC1 to the HIV-1 promoter. Collectively, these findings highlight ORC1 as a potential novel target implicated in HIV-1 latency and position it as a promising candidate for the development of novel LRAs. IMPORTANCE: Identifying host factors involved in maintaining human immunodeficiency virus type 1 (HIV-1) latency and understanding their mechanisms prepares the groundwork to discover novel targets for HIV-1 latent infection and provides further options for the selection of latency-reversing agents in the "shock" strategy. In this study, we identified a novel role of the DNA replication factor origin recognition complex 1 (ORC1) in maintaining repressive chromatin structures surrounding the HIV-1 promoter region, thereby contributing to HIV-1 latency. This discovery expands our understanding of the non-replicative functions of the ORC complex and provides a potential therapeutic strategy for HIV-1 cure.

KRAS4A directly regulates hexokinase 1.

The most frequently mutated oncogene in cancer is KRAS, which uses alternative fourth exons to generate two gene products (KRAS4A and KRAS4B) that differ only in their C-terminal membrane-targeting region1. Because oncogenic mutations occur in exons 2 or 3, two constitutively active KRAS proteins-each capable of transforming cells-are encoded when KRAS is activated by mutation2. No functional distinctions among the splice variants have so far been established. Oncogenic KRAS alters the metabolism of tumour cells3 in several ways, including increased glucose uptake and glycolysis even in the presence of abundant oxygen4 (the Warburg effect). Whereas these metabolic effects of oncogenic KRAS have been explained by transcriptional upregulation of glucose transporters and glycolytic enzymes3-5, it is not known whether there is direct regulation of metabolic enzymes. Here we report a direct, GTP-dependent interaction between KRAS4A and hexokinase 1 (HK1) that alters the activity of the kinase, and thereby establish that HK1 is an effector of KRAS4A. This interaction is unique to KRAS4A because the palmitoylation-depalmitoylation cycle of this RAS isoform enables colocalization with HK1 on the outer mitochondrial membrane. The expression of KRAS4A in cancer may drive unique metabolic vulnerabilities that can be exploited therapeutically.

DNA-Engineered Degradable Invisibility Cloaking for Tumor-Targeting Nanoparticles.

Nanoparticle (NP) delivery systems have been actively exploited for cancer therapy and vaccine development. Nevertheless, the major obstacle to targeted delivery lies in the substantial liver sequestration of NPs. Here we report a DNA-engineered approach to circumvent liver phagocytosis for enhanced tumor-targeted delivery of nanoagents in vivo. We find that a monolayer of DNA molecules on the NP can preferentially adsorb a dysopsonin protein in the serum to induce functionally invisibility to livers; whereas the tumor-specific uptake is triggered by the subsequent degradation of the DNA shell in vivo. The degradation rate of DNA shells is readily tunable by the length of coated DNA molecules. This DNA-engineered invisibility cloaking (DEIC) is potentially generic as manifested in both Ag2S quantum dot- and nanoliposome-based tumor-targeted delivery in mice. Near-infrared-II imaging reveals a high tumor-to-liver ratio of up to ∼5.1, approximately 18-fold higher than those with conventional nanomaterials. This approach may provide a universal strategy for high-efficiency targeted delivery of theranostic agents in vivo.

The construction of modular universal chimeric antigen receptor T (MU-CAR-T) cells by covalent linkage of allogeneic T cells and various antibody fragments.

BACKGROUND: Chimeric antigen receptor-T (CAR-T) cells therapy is one of the novel immunotherapeutic approaches with significant clinical success. However, their applications are limited because of long preparation time, high cost, and interpersonal variations. Although the manufacture of universal CAR-T (U-CAR-T) cells have significantly improved, they are still not a stable and unified cell bank. METHODS: Here, we tried to further improve the convenience and flexibility of U-CAR-T cells by constructing novel modular universal CAR-T (MU-CAR-T) cells. For this purpose, we initially screened healthy donors and cultured their T cells to obtain a higher proportion of stem cell-like memory T (TSCM) cells, which exhibit robust self-renewal capacity, sustainability and cytotoxicity. To reduce the alloreactivity, the T cells were further edited by double knockout of the T cell receptor (TCR) and class I human leukocyte antigen (HLA-I) genes utilizing the CRISPR/Cas9 system. The well-growing and genetically stable universal cells carrying the CAR-moiety were then stored as a stable and unified cell bank. Subsequently, the SDcatcher/GVoptiTag system, which generate an isopeptide bond, was used to covalently connect the purified scFvs of antibody targeting different antigens to the recovered CAR-T cells. RESULTS: The resulting CAR-T cells can perform different functions by specifically targeting various cells, such as the eradication of human immunodeficiency virus type 1 (HIV-1)-latenly-infected cells or elimination of T lymphoma cells, with similar efficiency as the traditional CAR-T cells did. CONCLUSION: Taken together, our strategy allows the production of CAR-T cells more modularization, and makes the quality control and pharmaceutic manufacture of CAR-T cells more feasible.

Development of nanobodies targeting hepatocellular carcinoma and application of nanobody-based CAR-T technology.

BACKGROUND: Chimeric antigen receptor T (CAR-T) cell therapy, as an emerging anti-tumor treatment, has garnered extensive attention in the study of targeted therapy of multiple tumor-associated antigens in hepatocellular carcinoma (HCC). However, the suppressive microenvironment and individual heterogeneity results in downregulation of these antigens in certain patients' cancer cells. Therefore, optimizing CAR-T cell therapy for HCC is imperative. METHODS: In this study, we administered FGFR4-ferritin (FGFR4-HPF) nanoparticles to the alpaca and constructed a phage library of nanobodies (Nbs) derived from alpaca, following which we screened for Nbs targeting FGFR4. Then, we conducted the functional validation of Nbs. Furthermore, we developed Nb-derived CAR-T cells and evaluated their anti-tumor ability against HCC through in vitro and in vivo validation. RESULTS: Our findings demonstrated that we successfully obtained high specificity and high affinity Nbs targeting FGFR4 after screening. And the specificity of Nbs targeting FGFR4 was markedly superior to their binding to other members of the FGFR family proteins. Furthermore, the Nb-derived CAR-T cells, targeting FGFR4, exhibited significantly enhanced anti-tumor efficacy in both experiments when in vitro and in vivo. CONCLUSIONS: In summary, the results of this study suggest that the CAR-T cells derived from high specificity and high affinity Nbs, targeting FGFR4, exhibited significantly enhanced anti-tumor efficacy in vitro and in vivo. This is an exploration of FGFR4 in the field of Nb-derived CAR-T cell therapy for HCC, holding promise for enhancing safety and effectiveness in the clinical treatment of HCC in the future.

CBX4 contributes to HIV-1 latency by forming phase-separated nuclear bodies and SUMOylating EZH2.

The retrovirus HIV-1 integrates into the host genome and establishes a latent viral reservoir that escapes immune surveillance. Molecular mechanisms of HIV-1 latency have been studied extensively to achieve a cure for the acquired immunodeficiency syndrome (AIDS). Latency-reversing agents (LRAs) have been developed to reactivate and eliminate the latent reservoir by the immune system. To develop more promising LRAs, it is essential to evaluate new therapeutic targets. Here, we find that CBX4, a component of the Polycomb Repressive Complex 1 (PRC1), contributes to HIV-1 latency in seven latency models and primary CD4+ T cells. CBX4 forms nuclear bodies with liquid-liquid phase separation (LLPS) properties on the HIV-1 long terminal repeat (LTR) and recruits EZH2, the catalytic subunit of PRC2. CBX4 SUMOylates EZH2 utilizing its SUMO E3 ligase activity, thereby enhancing the H3K27 methyltransferase activity of EZH2. Our results indicate that CBX4 acts as a bridge between the repressor complexes PRC1 and PRC2 that act synergistically to maintain HIV-1 latency. Dissolution of phase-separated CBX4 bodies could be a potential intervention to reactivate latent HIV-1.

Maternal depression and early childhood development among children aged 24-59 months: the mediating effect of responsive caregiving.

This study examined whether maternal depression is related to Early Childhood Developmental (ECD) delay among children by quantifying the mediating contribution of responsive caregiving. We used data from 1235 children (Children's mean age = 50.4 months; 582 girls, 653 boys, 93.9% were Han), selected through convenience sampling, in 2021. 4.7% of children had ECD delay, 34.3% of mothers had depression. Children with depressed mothers were less likely to receive responsive caregiving (OR 4.35, 95% CI 2.60-7.27), and those who did not receive responsive caregiving were more likely to experience ECD delay (OR 3.89, 95% CI 1.89-8.02). Responsive caregiving partly mediated the relationship between maternal depression and ECD. Early intervention for children with depressed mothers is worthy of further investigation.

Remote Sensing Image Classification Based on Canny Operator Enhanced Edge Features.

Remote sensing image classification plays a crucial role in the field of remote sensing interpretation. With the exponential growth of multi-source remote sensing data, accurately extracting target features and comprehending target attributes from complex images significantly impacts classification accuracy. To address these challenges, we propose a Canny edge-enhanced multi-level attention feature fusion network (CAF) for remote sensing image classification. The original image is specifically inputted into a convolutional network for the extraction of global features, while increasing the depth of the convolutional layer facilitates feature extraction at various levels. Additionally, to emphasize detailed target features, we employ the Canny operator for edge information extraction and utilize a convolution layer to capture deep edge features. Finally, by leveraging the Attentional Feature Fusion (AFF) network, we fuse global and detailed features to obtain more discriminative representations for scene classification tasks. The performance of our proposed method (CAF) is evaluated through experiments conducted across three openly accessible datasets for classifying scenes in remote sensing images: NWPU-RESISC45, UCM, and MSTAR. The experimental findings indicate that our approach based on incorporating edge detail information outperforms methods relying solely on global feature-based classifications.

Self-Assembled Ferritin Nanoparticles for Delivery of Antigens and Development of Vaccines: From Structure and Property to Applications.

Ferritin, an iron storage protein, is ubiquitously distributed across diverse life forms, fulfilling crucial roles encompassing iron retention, conversion, orchestration of cellular iron metabolism, and safeguarding cells against oxidative harm. Noteworthy attributes of ferritin include its innate amenability to facile modification, scalable mass production, as well as exceptional stability and safety. In addition, ferritin boasts unique physicochemical properties, including pH responsiveness, resilience to elevated temperatures, and resistance to a myriad of denaturing agents. Therefore, ferritin serves as the substrate for creating nanomaterials typified by uniform particle dimensions and exceptional biocompatibility. Comprising 24 subunits, each ferritin nanocage demonstrates self-assembly capabilities, culminating in the formation of nanostructures akin to intricate cages. Recent years have witnessed the ascendance of ferritin-based self-assembled nanoparticles, owing to their distinctive physicochemical traits, which confer substantial advantages and wide-ranging applications within the biomedical domain. Ferritin is highly appealing as a carrier for delivering drug molecules and antigen proteins due to its distinctive structural and biochemical properties. This review aims to highlight recent advances in the use of self-assembled ferritin as a novel carrier for antigen delivery and vaccine development, discussing the molecular mechanisms underlying its action, and presenting it as a promising and effective strategy for the future of vaccine development.

The impact of ultrasonic-assisted extraction on the in vitro hypoglycemic activity of peach gum polysaccharide in relation to its conformational conversion.

BACKGROUND: Peach gum (PG) is an exudate of the peach tree (Prunus persica of the Rosaceae family), which consists primarily of polysaccharides with a large molecular weight and branching structure. Consequently, PG can only swell in water and does not dissolve easily, which severely limits its application. Current conventional extraction methods for PG polysaccharide (PGPS) are time consuming and inefficient. This study investigated the impact of ultrasonic-assisted extraction (UAE) on PGPS structure and conformation, and their relationship to hypoglycemic activity in vitro. RESULTS: In comparison with conventional aqueous extraction, UAE enhanced PGPS yielded from 28.07-32.83% to 80.37-84.90% (w/w) in 2 h. It drastically decreased the molecular size and conformational parameters of PGPS, including weight-average molecular weight (Mw), number-average molecular weight (Mn), z-average radius of gyration (Rg), hydrodynamic radius (Rh) and instrinsic viscosity ([η]) values. Peach gum polysaccharide conformation converted extended molecules to flexible random coil chains or compact spheres with no obvious primary structure alteration. Furthermore, UAE altered the flow behavior of PGPS solution from that of a non-Newtonian fluid to that of a Newtonian fluid. As a result, PGPS treated with UAE displayed weaker inhibitory activity than untreated PGPS, mostly because UAE weakens the binding strength of PGPS to α-glucosidase. However, this negative effect of UAE on PGPS activity was compensated by the increased solubility of polysaccharide. This enabled PGPS to achieve a wider range of doses. CONCLUSION: Ultrasonic-assisted extraction is capable of degrading PGPS efficiently while preserving its primary structure, resulting in a Newtonian fluid solution. The degraded PGPS conformations displayed a consistent correlation with their inhibitory effect on α-glucosidase activity. © 2024 Society of Chemical Industry.

Small DNAs That Specifically and Tightly Bind Transition Metal Ions.

Specific DNA-binding to metal ions is a long-standing fundamental research topic with great potential to transform into nano/biotechnology and therapeutics applications. Herein, based on the mobility change of DNA in denaturing gels, we develop a selection strategy to discover a series of 40-45 nt small DNAs that can bind Zn2+ and Cd2+ specifically and tightly. The Zn2+- and Cd2+-bound DNA complexes can even tolerate harsh denaturing conditions of 8 M urea and 50 mM EDTA. The discovery not only exposes a new class of transition metal ion-binding DNAs but also provides potentially a new tool for targeting drug therapies based on metal ions.

Use of Bayesian decision analysis to maximize value in patient-centered randomized clinical trials in Parkinson's disease.

A fixed one-sided significance level of 5% is commonly used to interpret the statistical significance of randomized clinical trial (RCT) outcomes. While it is necessary to reduce the false positive rate, the threshold used could be chosen quantitatively and transparently to specifically reflect patient preferences regarding benefit-risk tradeoffs as well as other considerations. How can patient preferences be explicitly incorporated into RCTs in Parkinson's disease (PD), and what is the impact on statistical thresholds for device approval? In this analysis, we apply Bayesian decision analysis (BDA) to PD patient preference scores elicited from survey data. BDA allows us to choose a sample size (n) and significance level (α) that maximizes the overall expected value to patients of a balanced two-arm fixed-sample RCT, where the expected value is computed under both null and alternative hypotheses. For PD patients who had previously received deep brain stimulation (DBS) treatment, the BDA-optimal significance levels fell between 4.0% and 10.0%, similar to or greater than the traditional value of 5%. Conversely, for patients who had never received DBS, the optimal significance level ranged from 0.2% to 4.4%. In both of these populations, the optimal significance level increased with the severity of the patients' cognitive and motor function symptoms. By explicitly incorporating patient preferences into clinical trial designs and the regulatory decision-making process, BDA provides a quantitative and transparent approach to combine clinical and statistical significance. For PD patients who have never received DBS treatment, a 5% significance threshold may not be conservative enough to reflect their risk-aversion level. However, this study shows that patients who previously received DBS treatment present a higher tolerance to accept therapeutic risks in exchange for improved efficacy which is reflected in a higher statistical threshold.

Scaffold association factor B (SAFB) is required for expression of prenyltransferases and RAS membrane association.

Inhibiting membrane association of RAS has long been considered a rational approach to anticancer therapy, which led to the development of farnesyltransferase inhibitors (FTIs). However, FTIs proved ineffective against KRAS-driven tumors. To reveal alternative therapeutic strategies, we carried out a genome-wide CRISPR-Cas9 screen designed to identify genes required for KRAS4B membrane association. We identified five enzymes in the prenylation pathway and SAFB, a nuclear protein with both DNA and RNA binding domains. Silencing SAFB led to marked mislocalization of all RAS isoforms as well as RAP1A but not RAB7A, a pattern that phenocopied silencing FNTA, the prenyltransferase α subunit shared by farnesyltransferase and geranylgeranyltransferase type I. We found that SAFB promoted RAS membrane association by controlling FNTA expression. SAFB knockdown decreased GTP loading of RAS, abrogated alternative prenylation, and sensitized RAS-mutant cells to growth inhibition by FTI. Our work establishes the prenylation pathway as paramount in KRAS membrane association, reveals a regulator of prenyltransferase expression, and suggests that reduction in FNTA expression may enhance the efficacy of FTIs.

Self-assembly Induced Enhanced Electrochemiluminescence of Copper Nanoclusters Using DNA Nanoribbon Templates.

Copper nanoclusters (CuNCs) are attractive electrochemiluminescence (ECL) emitters as Cu is comparatively inexpensive, nontoxic, and highly abundant. However, their ECL yield is relatively low. Herein, we report that orderly self-assembly of CuNCs using DNA nanoribbon as the template (DNR/CuNCs) conferred the CuNCs with improved ECL properties compared with individual CuNCs in both annihilation and co-reactant processes. The DNR/CuNCs resulted in a high ECL yield of 46.8 % in K2 S2 O8 , which was ≈68 times higher than that of individual CuNCs. This strategy was successfully extended to other ECL emitters, such as gold nanoclusters and the Ru(bpy)3 2+ /TPrA system. Furthermore, as an application of DNR/CuNCs, a DNR/CuNC-based ECL biosensor with higher sensitivity was constructed for dopamine determination (two orders of magnitude lower than that previously reported), showing that DNR/CuNCs have a potential for application in ECL bioanalysis as a new type of superior luminophore candidate.

Contemporary outpatient management of patients with worsening heart failure with reduced ejection fraction: Rationale and design of the CHART-HF study.

BACKGROUND: Patients with heart failure with reduced ejection fraction (HFrEF) and worsening HF events (WHFE) represent a distinct subset of patients with a substantial comorbidity burden, greater potential for intolerance to medical therapy, and high risk of subsequent death, hospitalization and excessive healthcare costs. Although multiple therapies have been shown to be efficacious and safe in this high-risk population, there are limited real-world data regarding factors that impact clinical decision-making when initiating or modifying therapy. Likewise, prior analyses of US clinical practice support major gaps in medical therapy for HFrEF and few medication changes during longitudinal follow-up, yet granular data on reasons why clinicians do not initiate or up-titrate guideline-directed medication are lacking. METHODS: We designed the CHART-HF study, an observational study of approximately 1,500 patients comparing patients with and without WHFE (WHFE defined as receipt of intravenous diuretics in the inpatient, outpatient, or emergency department setting) who had an index outpatient visit in the US between 2017 and 2019. Patient-level data on clinical characteristics, clinical outcomes, and therapy will be collected from 2 data sources: a single integrated health system, and a national panel of cardiologists. Furthermore, clinician-reported rationale for treatment decisions and the factors prioritized with selection and optimization of therapies in real-world practice will be obtained. To characterize elements of clinician decision-making not documented in the medical record, the panel of cardiologists will review records of patients seen under their care to explicitly note their primary reason for initiating, discontinuing, and titrating medications specific medications, as well as the reason for not making changes to each medication during the outpatient visit. CONCLUSIONS: Results from CHART-HF have the potential to detail real-world US practice patterns regarding care of patients with HFrEF with versus without a recent WHFE, to examine clinician-reported reasons for use and non-use of guideline-directed medical therapy, and to characterize the magnitude and nature of clinical inertia toward evidence-based medication changes for HFrEF.

The efficacy of botulinum toxin A in the treatment of Raynaud's phenomenon in systemic sclerosis: A randomized self-controlled trial.

The current conservative and surgical treatments are not fully effective and have complications for Raynaud's phenomenon (RP) secondary to systemic sclerosis (SSc). Botulinum toxin A (BTX-A) can be used to manage RP, but the literature mostly includes case reports and case series. Thus, we performed a randomized controlled trial to explore the efficacy of BTX-A in the treatment of RP secondary to SSc. Sixteen patients with RP secondary to SSc were recruited. One hand was randomly included in the BTX-A group and the other as control. Both hands were tested before treatment and 4 weeks later using qualitative and quantitative dermatoscopic assessments and the cold water test. Reynolds score (from 6.7 ± 4.0 to 2.9 ± 3.7, p < 0.001), Tbase (from 25.8 ± 3.0°C to 27.9 ± 2.1°C, p = 0.031) and Tchange (from 2.1 ± 1.2°C to 4.5 ± 2.1°C, p < 0.001) in the experimental group were improved, while there were no improvements in Tbase and Tchange in the control group. In the experimental group, the sum of the six dermoscopic parameters was improved after treatment (from 4.00 (3.00, 5.75) to 3.00 (2.00, 5.00), p = 0.002); the nailfold capillary pattern staging was also improved (from 2.00 (2.00, 3.00) to 2.00 (1.00, 3.00), p = 0.004). There were no improvements in the dermoscopic assessment in the control group. None of the patients reported adverse reactions such as infection, hematoma, hand muscle weakness, allergic reaction and nerve injury. In conclusion, local injection BTX-A to treat RP secondary to SSc might be safe and effective.

High quality quasi-parallel x-ray microbeams based on a parabolic capillary.

High quality quasi-parallel x-ray microbeams have an appreciable application value in the x-ray diffraction analysis technique, which is currently one of the most significant non-destructive analysis techniques. A simulation of a parabolic single capillary is carried out based on the Monte Carlo simulation toolkit Geant4. The simulation results show that it is feasible to obtain high quality quasi-parallel x-ray microbeams based on a parabolic capillary and a traditional laboratorial x-ray source. We manufacture a parabolic capillary based on the simulation results. The physical parameters of the obtained x-ray beams are characterized by building an x-ray imaging system. The experimental results show that the x-ray beam with submicrometer size and almost zero divergence can be obtained from the traditional laboratorial x-ray source by utilizing a parabolic single capillary as a collimator.

Dual Discounting in Renewable Resource Planning under Risk.

Renewable resource planning and management projects entail evaluating economic and ecological criteria in the long term. During the past decade or so, dual discounting--ecological criteria discounted at a smaller rate than that for economic criteria--has been proposed for such projects as an alternative to the prevailing single-discounting scheme, out of theoretical and empirical considerations. We focus on how to apply this principle in planning problems that involve a multitude of risk in the attendant biological-economic system. A stochastic dynamic programming framework is introduced which allows dual discounting rates and finds the optimal decisions (passively) adapting to changes in the system. Furthermore, we show how to evaluate the variances of the criteria in this framework. With a case study of managing public forestlands in the US Pacific Northwestern region for both timber return and habitat preservation for the northern spotted owl (Strix occidentalis caurina), we illustrate the impacts that the dual-discounting scheme has on the trade-off between conflicting management objectives, the optimal planning strategy, the temporal development of the portion of the forestlands suitable for owl habitats, as well as its steady-state expected value and standard deviation.

Directing Multivalent Aptamer-Receptor Binding on the Cell Surface with Programmable Atom-Like Nanoparticles.

Multivalent interactions of biomolecules play pivotal roles in physiological and pathological settings. Whereas the directionality of the interactions is crucial, the state-of-the-art synthetic multivalent ligand-receptor systems generally lack programmable approaches for orthogonal directionality. Here, we report the design of programmable atom-like nanoparticles (aptPANs) to direct multivalent aptamer-receptor binding on the cell interface. The positions of the aptamer motifs can be prescribed on tetrahedral DNA frameworks to realize atom-like orthogonal valence and direction, enabling the construction of multivalent molecules with fixed aptamer copy numbers but different directionality. These directional-yet-flexible aptPAN molecules exhibit the adaptability to the receptor distribution on cell surfaces. We demonstrate the high-affinity tumor cell binding with a linear aptPAN oligomer (≈13-fold improved compared to free aptamers), which leads to ≈50 % suppression of cell growth.