CRISPR/Cas9-based split homing gene drive targeting doublesex for population suppression of the global fruit pest Drosophila suzukii.

Genetic-based methods offer environmentally friendly species-specific approaches for control of insect pests. One method, CRISPR homing gene drive that target genes essential for development, could provide very efficient and cost-effective control. While significant progress has been made in developing homing gene drives for mosquito disease vectors, little progress has been made with agricultural insect pests. Here, we report the development and evaluation of split homing drives that target the doublesex (dsx) gene in Drosophila suzukii, an invasive pest of soft-skinned fruits. The drive component, consisting of dsx single guide RNA and DsRed genes, was introduced into the female-specific exon of dsx, which is essential for function in females but not males. However, in most strains, hemizygous females were sterile and produced the male dsx transcript. With a modified homing drive that included an optimal splice acceptor site, hemizygous females from each of the four independent lines were fertile. High transmission rates of the DsRed gene (94 to 99%) were observed with a line that expressed Cas9 with two nuclear localization sequences from the D. suzukii nanos promoter. Mutant alleles of dsx with small in-frame deletions near the Cas9 cut site were not functional and thus would not provide resistance to drive. Finally, mathematical modeling showed that the strains could be used for suppression of lab cage populations of D. suzukii with repeated releases at relatively low release ratios (1:4). Our results indicate that the split CRISPR homing gene drive strains could potentially provide an effective means for control of D. suzukii populations.

Remote control of mechanochemical reactions under physiological conditions using biocompatible focused ultrasound.

External control of chemical reactions in biological settings with spatial and temporal precision is a grand challenge for noninvasive diagnostic and therapeutic applications. While light is a conventional stimulus for remote chemical activation, its penetration is severely attenuated in tissues, which limits biological applicability. On the other hand, ultrasound is a biocompatible remote energy source that is highly penetrant and offers a wide range of functional tunability. Coupling ultrasound to the activation of specific chemical reactions under physiological conditions, however, remains a challenge. Here, we describe a synergistic platform that couples the selective mechanochemical activation of mechanophore-functionalized polymers with biocompatible focused ultrasound (FUS) by leveraging pressure-sensitive gas vesicles (GVs) as acousto-mechanical transducers. The power of this approach is illustrated through the mechanically triggered release of covalently bound fluorogenic and therapeutic cargo molecules from polymers containing a masked 2-furylcarbinol mechanophore. Molecular release occurs selectively in the presence of GVs upon exposure to FUS under physiological conditions. These results showcase the viability of this system for enabling remote control of specific mechanochemical reactions with spatiotemporal precision in biologically relevant settings and demonstrate the translational potential of polymer mechanochemistry.

A small proton charge radius from an electron-proton scattering experiment.

Elastic electron-proton scattering (e-p) and the spectroscopy of hydrogen atoms are the two methods traditionally used to determine the proton charge radius, rp. In 2010, a new method using muonic hydrogen atoms1 found a substantial discrepancy compared with previous results2, which became known as the 'proton radius puzzle'. Despite experimental and theoretical efforts, the puzzle remains unresolved. In fact, there is a discrepancy between the two most recent spectroscopic measurements conducted on ordinary hydrogen3,4. Here we report on the proton charge radius experiment at Jefferson Laboratory (PRad), a high-precision e-p experiment that was established after the discrepancy was identified. We used a magnetic-spectrometer-free method along with a windowless hydrogen gas target, which overcame several limitations of previous e-p experiments and enabled measurements at very small forward-scattering angles. Our result, rp = 0.831 ± 0.007stat ± 0.012syst femtometres, is smaller than the most recent high-precision e-p measurement5 and 2.7 standard deviations smaller than the average of all e-p experimental results6. The smaller rp we have now measured supports the value found by two previous muonic hydrogen experiments1,7. In addition, our finding agrees with the revised value (announced in 2019) for the Rydberg constant8-one of the most accurately evaluated fundamental constants in physics.

Multimechanophore Polymers for Mechanically Triggered Small Molecule Release with Ultrahigh Payload Capacity.

Polymers that release small molecules in response to mechanical force are promising for a variety of applications including drug delivery, catalysis, and sensing. While a number of mechanophores have been developed for the release of covalently bound payloads, existing strategies are either limited in cargo scope or, in the case of more general mechanophore designs, are restricted to the release of one or two cargo molecules per polymer chain. Herein, we introduce a nonscissile mechanophore based on a masked 2-furylcarbinol derivative that enables the preparation of multimechanophore polymers with ultrahigh payload capacity. We demonstrate that polymers prepared via ring-opening metathesis polymerization are capable of releasing hundreds of small-molecule payloads per polymer chain upon ultrasound-induced mechanochemical activation. This nonscissile masked 2-furylcarbinol mechanophore overcomes a major challenge in cargo loading capacity associated with previous 2-furylcarbinol mechanophore designs, enabling applications that benefit from much higher concentrations of delivered cargo.

Mechanically Triggered Bright Chemiluminescence from Polymers by Exploiting a Synergy between Masked 2-Furylcarbinol Mechanophores and 1,2-Dioxetane Chemiluminophores.

Mechanoluminescence, or the generation of light from materials under external force, is a powerful tool for biology and materials science. However, direct mechanoluminescence from polymers remains limited. Here, we report a novel design strategy for mechanoluminescent polymers that leverages the synergy between a masked 2-furylcarbinol mechanophore for mechanically triggered release and an adamantylidene-phenoxy-1,2-dioxetane chemiluminophore payload. Ultrasound-induced mechanochemical activation of polymers, in both organic and aqueous solutions, triggers a cascade reaction that ultimately results in bright green light emission. This novel strategy capitalizes on the modularity of the masked 2-furylcarbinol mechanophore system in combination with advances in the design of exceptionally bright and highly tunable adamantylidene-1,2-dioxetane chemiluminophores. We anticipate that this chemistry will enable diverse applications in optoelectronics, sensing, bioimaging, optogenetics, and many other areas.

The changing landscape of text mining: a review of approaches for ecology and evolution.

In ecology and evolutionary biology, the synthesis and modelling of data from published literature are commonly used to generate insights and test theories across systems. However, the tasks of searching, screening, and extracting data from literature are often arduous. Researchers may manually process hundreds to thousands of articles for systematic reviews, meta-analyses, and compiling synthetic datasets. As relevant articles expand to tens or hundreds of thousands, computer-based approaches can increase the efficiency, transparency and reproducibility of literature-based research. Methods available for text mining are rapidly changing owing to developments in machine learning-based language models. We review the growing landscape of approaches, mapping them onto three broad paradigms (frequency-based approaches, traditional Natural Language Processing and deep learning-based language models). This serves as an entry point to learn foundational and cutting-edge concepts, vocabularies, and methods to foster integration of these tools into ecological and evolutionary research. We cover approaches for modelling ecological texts, generating training data, developing custom models and interacting with large language models and discuss challenges and possible solutions to implementing these methods in ecology and evolution.

Expansion of the genetic toolbox for manipulation of the global crop pest Drosophila suzukii: Isolation and assessment of eye colour mutant strains.

Drosophila suzukii (Matsumura) (Diptera: Drosophilidae), commonly called spotted wing Drosophila, is an important agricultural pest recognised worldwide. D. suzukii is a pest of soft-skinned fruits as females can lay eggs in ripening fruit before harvest. While strains for genetic biocontrol of D. suzukii have been made, the development of transgenic D. suzukii strains and their further screening remain a challenge partly due to the lack of phenotypically trackable genetic-markers, such as those widely used with the model genetic organism D. melanogaster. Here, we have used CRISPR/Cas9 to introduce heritable mutations in the eye colour genes white, cinnabar and sepia, which are located on the X, second and third chromosomes, respectively. Strains were obtained, which were homozygous for a single mutation. Genotyping of the established strains showed insertion and/or deletions (indels) at the targeted sites. A strain homozygous for mutations in cinnabar and sepia showed a pale-yellow eye colour at eclosion but darkened to a sepia colour after a week. The fecundity and fertility of some of the cinnabar and sepia strains were comparable with the wild type. Although white mutant males were previously reported to be sterile, we found that sterility is not fully penetrant and we have been able to maintain white-eyed strains for over a year. The cinnabar, sepia and white mutant strains developed in this study should facilitate future genetic studies in D. suzukii and the development of strains for genetic control of this pest.

Aberrant brain network topology in youth with a familial risk for bipolar disorder: a task-based fMRI connectome study.

BACKGROUND: Youth with a family history of bipolar disorder (BD) may be at increased risk for mood disorders and for developing side effects after antidepressant exposure. The neurobiological basis of these risks remains poorly understood. We aimed to identify biomarkers underlying risk by characterizing abnormalities in the brain connectome of symptomatic youth at familial risk for BD. METHODS: Depressed and/or anxious youth (n = 119, age = 14.9 ± 1.6 years) with a family history of BD but no prior antidepressant exposure and typically developing controls (n = 57, age = 14.8 ± 1.7 years) received functional magnetic resonance imaging (fMRI) during an emotional continuous performance task. A generalized psychophysiological interaction (gPPI) analysis was performed to compare their brain connectome patterns, followed by machine learning of topological metrics. RESULTS: High-risk youth showed weaker connectivity patterns that were mainly located in the default mode network (DMN) (network weight = 50.1%) relative to controls, and connectivity patterns derived from the visual network (VN) constituted the largest proportion of aberrant stronger pairs (network weight = 54.9%). Global local efficiency (Elocal, p = .022) and clustering coefficient (Cp, p = .029) and nodal metrics of the right superior frontal gyrus (SFG) (Elocal: p < .001; Cp: p = .001) in the high-risk group were significantly higher than those in healthy subjects, and similar patterns were also found in the left insula (degree: p = .004; betweenness: p = .005; age-by-group interaction, p = .038) and right hippocampus (degree: p = .003; betweenness: p = .003). The case-control classifier achieved a cross-validation accuracy of 78.4%. CONCLUSIONS: Our findings of abnormal connectome organization in the DMN and VN may advance mechanistic understanding of risk for BD. Neuroimaging biomarkers of increased network segregation in the SFG and altered topological centrality in the insula and hippocampus in broader limbic systems may be used to target interventions tailored to mitigate the underlying risk of brain abnormalities in these at-risk youth.

The ethics of firing unvaccinated employees.

Some organisations make vaccination a condition of employment. This means prospective employees must demonstrate they have been vaccinated (eg, against measles) to be hired. But it also means organisations must decide whether existing employees should be expected to meet newly introduced vaccination conditions (eg, against COVID-19). Unlike prospective employees who will not be hired if they do not meet vaccination conditions, existing employees who fail to meet new vaccination conditions risk being fired The latter seems worse than the former. Hence, objections to vaccination mandates commonly centre on the harms that will be visited on existing employees who are unwilling to be vaccinated. However, because this objection does not necessarily entail the claim that vaccination is unnecessary for the effective and safe performance of certain jobs, those making this objection should have less of an objection, or no objection at all (at least on these grounds), to introducing vaccination requirements in some cases for prospective employees. Yet, in this paper, I shall argue that if one has reason to believe vaccination requirements can be justified for prospective employees, one should also believe they are justified for existing employees despite any asymmetry in consequences experienced by the two groups. As a consequence, common objections made against vaccination mandates grounded solely in the harms that may be experienced by existing employees who are unwilling to be vaccinated should be considered unpersuasive.

Fates of attached E. coli o157:h7 on intact leaf surfaces revealed leafy green susceptibility.

Leafy greens, especially lettuce, are repeatedly linked to foodborne outbreaks. This paper studied the susceptibility of different leafy greens to human pathogens. Five commonly consumed leafy greens, including romaine lettuce, green-leaf lettuce, baby spinach, kale, and collard, were selected by their outbreak frequencies. The behavior of E. coli O157:H7 87-23 on intact leaf surfaces and in their lysates was investigated. Bacterial attachment was positively correlated with leaf surface roughness and affected by the epicuticular wax composition. At room temperature, E. coli O157:H7 had the best growth potentials on romaine and green-leaf lettuce surfaces. The bacterial growth was positively correlated with stomata size and affected by epicuticular wax compositions. At 37 °C, E. coli O157:H7 87-23 was largely inhibited by spinach and collard lysates, and it became undetectable in kale lysate after 24 h of incubation. Kale and collard lysates also delayed or partially inhibited the bacterial growth in TSB and lettuce lysate at 37 °C, and they sharply reduced the E. coli O157:H7 population on green leaf lettuce at 4 °C. In summary, the susceptibility of leafy greens to E. coli O157:H7 is determined by a produce-specific combination of physiochemical properties and temperature.

Conditional knockdown of transformer in sheep blow fly suggests a role in repression of dosage compensation and potential for population suppression.

The transformer (tra) gene is essential for female development in many insect species, including the Australian sheep blow fly, Lucilia cuprina. Sex-specific tra RNA splicing is controlled by Sex lethal (Sxl) in Drosophila melanogaster but is auto-regulated in L. cuprina. Sxl also represses X chromosome dosage compensation in female D. melanogaster. We have developed conditional Lctra RNAi knockdown strains using the tet-off system. Four strains did not produce females on diet without tetracycline and could potentially be used for genetic control of L. cuprina. In one strain, which showed both maternal and zygotic tTA expression, most XX transformed males died at the pupal stage. RNAseq and qRT-PCR analyses of mid-stage pupae showed increased expression of X-linked genes in XX individuals. These results suggest that Lctra promotes somatic sexual differentiation and inhibits X chromosome dosage compensation in female L. cuprina. However, XX flies homozygous for a loss-of-function Lctra knockin mutation were fully transformed and showed high pupal eclosion. Two of five X-linked genes examined showed a significant increase in mRNA levels in XX males. The stronger phenotype in the RNAi knockdown strain could indicate that maternal Lctra expression may be essential for initiation of dosage compensation suppression in female embryos.

"She was finally mine": the moral experience of families in the context of trisomy 13 and 18- a scoping review with thematic analysis.

INTRODUCTION: The value of a short life characterized by disability has been hotly debated in the literature on fetal and neonatal outcomes. METHODS: We conducted a scoping review to summarize the available empirical literature on the experiences of families in the context of trisomy 13 and 18 (T13/18) with subsequent thematic analysis of the 17 included articles. FINDINGS: Themes constructed include (1) Pride as Resistance, (2) Negotiating Normalcy and (3) The Significance of Time. INTERPRETATION: Our thematic analysis was guided by the moral experience framework conceived by Hunt and Carnevale (2011) in association with the VOICE (Views On Interdisciplinary Childhood Ethics) collaborative research group. RELEVANCE: This article will be of interest and value to healthcare professionals and bioethicists who support families navigating the medically and ethically complex landscape of T13/18.

Unique yellow shifts for small and brief stimuli in the central retina.

The spectral locus of unique yellow was determined for flashes of different sizes (<11 arcmin) and durations (<500 ms) presented in and near the fovea. An adaptive optics scanning laser ophthalmoscope was used to minimize the effects of higher-order aberrations during simultaneous stimulus delivery and retinal imaging. In certain subjects, parafoveal cones were classified as L, M, or S, which permitted the comparison of unique yellow measurements with variations in local L/M ratios within and between observers. Unique yellow shifted to longer wavelengths as stimulus size or duration was reduced. This effect is most pronounced for changes in size and more apparent in the fovea than in the parafovea. The observed variations in unique yellow are not entirely predicted from variations in L/M ratio and therefore implicate neural processes beyond photoreception.

Cost analysis of one-time intravenous antibiotic doses in the emergency department.

BACKGROUND: Research shows that one-time doses of intravenous (IV) antibiotics do not improve resolution of infection. Providers, however, continue to use them - especially in the emergency department. Very few studies have aimed to quantify the cost of this practice. OBJECTIVES: The primary objective was to evaluate the difference in average total cost of emergency department (ED) stay between patients who received a one-time dose of intravenous antibiotics in the ED before discharging on oral antibiotics and patients who were just discharged on oral antibiotics. Secondary objectives were to evaluate the differences in durations of stay between the two groups, as well as the differences in adverse drug effects and need for healthcare contact after discharge. METHODS: Chart review was conducted to identify patients who received and did not receive a one-time dose of IV antibiotics in the ED between April 30, 2020, and April 30, 2022. A micro-costing approach was used to determine ED-associated costs per patient. Comparisons in primary and secondary outcomes were performed using statistical inferential tests. RESULTS: A total of 102 patients were analyzed in each group. Patients who received a one-time dose of intravenous antibiotics in the emergency department before being discharged on oral antibiotics had an average length of stay of 4.55 hours, as opposed to patients who did not receive a one-time dose of intravenous antibiotics before being discharged on oral antibiotics who had an average length of stay of 2.82 hours (absolute difference: 1.73 hours, p < 0.001). One-time dosing of intravenous antibiotics in the emergency department incurred an additional cost of approximately $556 per patient, totaling to over $56,000 in our study cohort. CONCLUSION: The use of one-time intravenous antibiotics in the emergency department did not confer any additional benefits to patients. Use of one-time doses resulted in significantly reduced throughput in the emergency department and significantly increased healthcare costs.

Parauchenoglanis stiassnyae (Siluriformes: Auchenoglanididae): A new species of giraffe catfish from Mfimi-Lukenie basin, central Africa, Democratic Republic of Congo.

A new, distinctively short-bodied giraffe catfish of Parauchenoglanis is described from the Ndzaa River, a small left-bank tributary of the Mfimi-Lukenie basin in the Central basin of the Congo River in the Democratic Republic of the Congo. The new species can be distinguished from all congeners by having 29 or fewer (vs. 33 or more) total vertebrae. It can further be distinguished from all congeners, except Parauchenoglanis zebratus Sithole et al., 2023 and Parauchenoglanis ngamensis (Boulenger 1911), by having 13 or 14 (vs. 16 or more) pre-anal vertebrae. The species is endemic to the Mfimi River basin, where it has been collected mainly in blackwater tributaries.

Shared Protentions in Multi-Agent Active Inference.

In this paper, we unite concepts from Husserlian phenomenology, the active inference framework in theoretical biology, and category theory in mathematics to develop a comprehensive framework for understanding social action premised on shared goals. We begin with an overview of Husserlian phenomenology, focusing on aspects of inner time-consciousness, namely, retention, primal impression, and protention. We then review active inference as a formal approach to modeling agent behavior based on variational (approximate Bayesian) inference. Expanding upon Husserl's model of time consciousness, we consider collective goal-directed behavior, emphasizing shared protentions among agents and their connection to the shared generative models of active inference. This integrated framework aims to formalize shared goals in terms of shared protentions, and thereby shed light on the emergence of group intentionality. Building on this foundation, we incorporate mathematical tools from category theory, in particular, sheaf and topos theory, to furnish a mathematical image of individual and group interactions within a stochastic environment. Specifically, we employ morphisms between polynomial representations of individual agent models, allowing predictions not only of their own behaviors but also those of other agents and environmental responses. Sheaf and topos theory facilitates the construction of coherent agent worldviews and provides a way of representing consensus or shared understanding. We explore the emergence of shared protentions, bridging the phenomenology of temporal structure, multi-agent active inference systems, and category theory. Shared protentions are highlighted as pivotal for coordination and achieving common objectives. We conclude by acknowledging the intricacies stemming from stochastic systems and uncertainties in realizing shared goals.

An intrinsically disordered transcription activation domain increases the DNA binding affinity and reduces the specificity of NFκB p50/RelA.

Many transcription factors contain intrinsically disordered transcription activation domains (TADs), which mediate interactions with coactivators to activate transcription. Historically, DNA-binding domains and TADs have been considered as modular units, but recent studies have shown that TADs can influence DNA binding. Whether these results can be generalized to more TADs is not clear. Here, we biophysically characterized the NFκB p50/RelA heterodimer including the RelA TAD and investigated the TAD's influence on NFκB-DNA interactions. In solution, we show the RelA TAD is disordered but compact, with helical tendency in two regions that interact with coactivators. We determined that the presence of the TAD increased the stoichiometry of NFκB-DNA complexes containing promoter DNA sequences with tandem κB recognition motifs by promoting the binding of NFκB dimers in excess of the number of κB sites. In addition, we measured the binding affinity of p50/RelA for DNA containing tandem κB sites and single κB sites. While the presence of the TAD enhanced the binding affinity of p50/RelA for all κB sequences tested, it also increased the affinity for nonspecific DNA sequences by over 10-fold, leading to an overall decrease in specificity for κB DNA sequences. In contrast, previous studies have generally reported that TADs decrease DNA-binding affinity and increase sequence specificity. Our results reveal a novel function of the RelA TAD in promoting binding to nonconsensus DNA, which sheds light on previous observations of extensive nonconsensus DNA binding by NFκB in vivo in response to strong inflammatory signals.

Ultrahigh-Throughput Directed Evolution of Polymer-Degrading Enzymes Using Yeast Display.

Enzymes that degrade synthetic polymers have attracted intense interest for eco-friendly plastic recycling. However, because enzymes did not evolve for the cleavage of abiotic polymers, directed evolution strategies are needed to enhance activity for plastic degradation. Previous directed evolution efforts relied on polymer degradation assays that were limited to screening ∼104 mutants. Here, we report a high-throughput yeast surface display platform to rapidly evaluate >107 enzyme mutants for increased activity in cleaving synthetic polymers. In this platform, individual yeast cells display distinct mutants, and enzyme activity is detected by a change in fluorescence upon the cleavage of a synthetic probe resembling a polymer of interest. Highly active mutants are isolated by fluorescence activated cell sorting and identified through DNA sequencing. To demonstrate this platform, we performed directed evolution of a polyethylene terephthalate (PET)-depolymerizing enzyme, leaf and branch compost cutinase (LCC). We identified activity-boosting mutations that substantially increased the kinetics of degradation of solid PET films. Biochemical assays and molecular dynamics (MD) simulations of the most active variants suggest that the H218Y mutation improves the binding of the enzyme to PET. Overall, this evolution platform increases the screening throughput of polymer-degrading enzymes by 3 orders of magnitude and identifies mutations that enhance kinetics for depolymerizing solid substrates.

Divergent Total Synthesis and Characterization of Maxamycins.

A new streamlined and scaled divergent total synthesis of pocket-modified vancomycin analogs is detailed that provides a common late-stage intermediate [Ψ[C(═S)NH]Tpg4]vancomycin (LLS = 18 steps, 12% overall yield, >5 g prepared) to access both existing and future pocket modifications. Highlights of the approach include an atroposelective synthesis of [Ψ[C(═S)NH]Tpg4]vancomycin aglycon (11), a one-pot enzymatic glycosylation for direct conversion to [Ψ[C(═S)NH]Tpg4]vancomycin (12), and new powerful methods for the late-stage conversion of the embedded thioamide to amidine/aminomethylene pocket modifications. Incorporation of two peripheral modifications provides a scalable total synthesis of the maxamycins, all prepared from aglycon 11 without use of protecting groups. Thus, both existing and presently unexplored pocket-modified analogues paired with a range of peripheral modifications are accessible from this common thioamide intermediate. In addition to providing an improved synthesis of the initial member of the maxamycins, this is illustrated herein with the first synthesis and examination of maxamycins that contain the most effective of the pocket modifications (amidine) described to date combined with two additional peripheral modifications. These new amidine-based maxamycins proved to be potent, durable, and efficacious antimicrobial agents that display equipotent activity against vancomycin-sensitive and vancomycin-resistant Gram-positive organisms and act by three independent synergistic mechanisms of action. In the first such study conducted to date, one new maxamycin (21, MX-4) exhibited efficacious in vivo activity against a feared and especially challenging multidrug-resistant (MRSA) and vancomycin-resistant (VRSA) S. aureus bacterial strain (VanA VRS-2) for which vancomycin is inactive.

Chemoselective, Oxidation-Induced Macrocyclization of Tyrosine-Containing Peptides.

Inspired by nature's wide range of oxidation-induced modifications to install cross-links and cycles at tyrosine (Tyr) and other phenol-containing residue side chains, we report a Tyr-selective strategy for the preparation of Tyr-linked cyclic peptides. This approach leverages N4-substituted 1,2,4-triazoline-3,5-diones (TADs) as azo electrophiles that react chemoselectively with the phenolic side chain of Tyr residues to form stable C-N1-linked cyclic peptides. In the developed method, a precursor 1,2,4-triazolidine-3,5-dione moiety, also known as urazole, is readily constructed at any free amine revealed on a solid-supported peptide. Once prepared, the N4-substituted urazole peptide is selectively oxidized using mild, peptide-compatible conditions to generate an electrophilic N4-substituted TAD peptide intermediate that reacts selectively under aqueous conditions with internal and terminal Tyr residues to furnish Tyr-linked cyclic peptides. The approach demonstrates good tolerance of native residue side chains and enables access to cyclic peptides ranging from 3- to 11-residues in size (16- to 38-atom-containing cycles). The identity of the installed Tyr-linkage, a stable covalent C-N1 bond, was characterized using NMR spectroscopy. Finally, we applied the developed method to prepare biologically active Tyr-linked cyclic peptides bearing the integrin-binding RGDf epitope.