[99mTc]Tc-PentixaTec: development, extensive pre-clinical evaluation, and first human experience

Purpose The clinical success non-invasive imaging of CXCR4 expression using [(68) Ga]Ga-PentixaFor-PET warrants an expansion of the targeting concept towards conventional scintigraphy/SPECT with their lower cost and general availability. To this aim, we developed and comparatively evaluated a series of Tc-99m-labeled cyclic pentapeptides based on the PentixaFor scaffold.Methods Six mas(3)-conjugated CPCR4 analogs with different 4-aminobenzoic acid (Abz)-D-Ala-D-Arg-aa(3) linkers (L1-L6) as well as the corresponding HYNIC- and N-4-analogs of L6-CPCR4 were synthesized via standard SPPS. Competitive binding studies (IC50 and IC(50)inv) were carried out using Jurkat T cell lymphoma cells and [I-125]FC-131 as radioligand. Internalization kinetics were investigated using hCXCR4-overexpressing Chem-1 cells. Biodistribution studies and small animal SPECT/CT imaging (1 h p.i.) were carried out using Jurkat xenograft bearing CB17/SCID mice. Based on the preclinical results, [Tc-99m]Tc-N-4-L6-CPCR4 ([Tc-99m]Tc-PentixaTec) was selected for an early translation to the human setting. Five patients with hematologic malignancies underwent [Tc-99m]Tc-N-4-L6-CPCR4 SPECT/planar imaging with individual dosimetry.Results Of the six mas(3)-conjugated peptides, mas(3)-L6-CPCR4 (mas(3)-dap-r-a-Abz-CPCR4) showed the highest CXCR4 affinity (IC50 = 5.0 & PLUSMN; 1.3 nM). Conjugation with N-4 (N-4-L6-CPCR4) further improved hCXCR4 affinity to 0.6 & PLUSMN; 0.1 nM. [Tc-99m]Tc-N-4-L6-CPCR4 also showed the most efficient internalization (97% of total cellular activity at 2 h) and the highest tumor accumulation (8.6 & PLUSMN; 1.3% iD/g, 1 h p.i.) of the compounds investigated. Therefore, [Tc-99m]Tc-N-4-L6-CPCR4 (termed [Tc-99m]Tc-PentixaTec) was selected for first-in-human application. [Tc-99m]Tc-PentixaTec was well tolerated, exhibits a favorable biodistribution and dosimetry profile (2.1-3.4 mSv per 500 MBq) and excellent tumor/background ratios in SPECT and planar imaging.Conclusion The successive optimization of the amino acid composition of the linker structure and the N-terminal Tc-99m-labeling strategies (mas(3) vs HYNIC vs N-4) has provided [Tc-99m]Tc-PentixaTec as a novel, highly promising CXCR4-targeted SPECT agent for clinical application. With its excellent CXCR4 affinity, efficient internalization, high uptake in CXCR4-expressing tissues, suitable clearance/biodistribution characteristics, and favorable human dosimetry, it holds great potential for further clinical use

Predicting dispersal of auto-gyrating fruit in tropical trees : a case study from the Dipterocarpaceae

Acknowledgments We thank the Sabah Forestry Department for access to SFR and the Rainforest Discovery Center for use of the canopy tower. JRS is funded by the Swiss National Science Foundation (SNF) grant number PDFMP3_132479/1. We are grateful for the comments of two anonymous reviewers which greatly improved the manuscript.Peer reviewedPublisher PD

Internal stress distribution in weld-affected zone under the effect of constrained loads

The paper presents the experimental results of identify the redistribution pattern under the influence of mechanic cycle loads. The subject of the research was the weld metal zone of the uniform joint made of steel X12Cr1MoV. The research method was to organize the mechanic cyclic deformation of sample and to increase the load in each regular load cycle. The result of the work is the determination of sign-variable pattern of internal stress changes under deformation leading to propagation of fatigue and destruction

Responding to food, environment and health challenges by changing meat consumption behaviours in consumers

Current meat consumption levels impact environment and health, highlighting a need to reduce meat consumption and increase that of plant‐based alternative proteins. There appears to be a lack of awareness amongst consumers as to how meat consumption affects health and climate change, which is likely to undermine intention to change. Of those who intend to change, many do not translate that intention to reduce meat consumption into behaviour change. Consumers appear open to the notion of reducing meat consumption but lack the knowledge, motivation or capability to make such changes. For many, meat eating is a traditional social practice, re‐enforced by economics, ecological, technological and institutional factors, including media and marketing. Many food choices are not logical reasoned actions but subconscious, automatic, rapid decisions, relying on heuristic processing and heavily influenced by contextual cues. Promising targets for changing individual consumption patterns could focus on closing the awareness‐intention and intention‐behaviour gaps. Modifying contextual determinants of food choice, highlighting personally relevant internal motivators related to individual requirements, and aligning such messages with positive re‐enforcement about animal welfare and environment would close the awareness‐intention gap. A framework of reference for a healthy, sustainable diet, improvements in the range, sensory attributes, convenience and ease of use of meat substitutes, reduction in the meat portion components of ready meals (by substitution with other foods), reformulation of processed products to include a greater proportion of non‐meat proteins, economic incentives and emphasis on the benefits to environment and animal welfare could reduce the intention‐behaviour gap. Better alignment of environmental and health messages would concentrate public health messages and effort to create a market environment that facilitates sustainable food choices to produce moderate population level wide‐scale changes in plant protein consumption, with significant impact on health and environmental outcomes

Caterpillars and fungal pathogens: two co-occurring parasites of an ant-plant mutualism

In mutualisms, each interacting species obtains resources from its partner that it would obtain less efficiently if alone, and so derives a net fitness benefit. In exchange for shelter (domatia) and food, mutualistic plant-ants protect their host myrmecophytes from herbivores, encroaching vines and fungal pathogens. Although selective filters enable myrmecophytes to host those ant species most favorable to their fitness, some insects can by-pass these filters, exploiting the rewards supplied whilst providing nothing in return. This is the case in French Guiana for Cecropia obtusa (Cecropiaceae) as Pseudocabima guianalis caterpillars (Lepidoptera, Pyralidae) can colonize saplings before the installation of their mutualistic Azteca ants. The caterpillars shelter in the domatia and feed on food bodies (FBs) whose production increases as a result. They delay colonization by ants by weaving a silk shield above the youngest trichilium, where the FBs are produced, blocking access to them. This probable temporal priority effect also allows female moths to lay new eggs on trees that already shelter caterpillars, and so to occupy the niche longer and exploit Cecropia resources before colonization by ants. However, once incipient ant colonies are able to develop, they prevent further colonization by the caterpillars. Although no higher herbivory rates were noted, these caterpillars are ineffective in protecting their host trees from a pathogenic fungus, Fusarium moniliforme (Deuteromycetes), that develops on the trichilium in the absence of mutualistic ants. Therefore, the Cecropia treelets can be parasitized by two often overlooked species: the caterpillars that shelter in the domatia and feed on FBs, delaying colonization by mutualistic ants, and the fungal pathogen that develops on old trichilia. The cost of greater FB production plus the presence of the pathogenic fungus likely affect tree growth

Relationship between Reproductive Allocation and Relative Abundance among 32 Species of a Tibetan Alpine Meadow: Effects of Fertilization and Grazing

Background: Understanding the relationship between species traits and species abundance is an important goal in ecology and biodiversity science. Although theoretical studies predict that traits related to performance (e.g. reproductive allocation) are most directly linked to species abundance within a community, empirical investigations have rarely been done. It also remains unclear how environmental factors such as grazing or fertilizer application affect the predicted relationship. Methodology: We conducted a 3-year field experiment in a Tibetan alpine meadow to assess the relationship between plant reproductive allocation (RA) and species relative abundance (SRA) on control, grazed and fertilized plots. Overall, the studied plant community contained 32 common species. Principal Findings: At the treatment level, (i) RA was negatively correlated with SRA on control plots and during the first year on fertilized plots. (ii) No negative RA–SRA correlations were observed on grazed plots and during the second and third year on fertilized plots. (iii) Seed size was positively correlated with SRA on control plots. At the plot level, the correlation between SRA and RA were not affected by treatment, year or species composition. Conclusions/Significance: Our study shows that the performance-related trait RA can negatively affect SRA within communities, which is possibly due to the tradeoffs between clonal growth (for space occupancy) and sexual reproduction. We propose that if different species occupy different positions along these tradeoffs it will contribute to biodiversity maintenance in local communities or even at lager scale

Ecological autocatalysis:A central principle in ecosystem organization?

Ecosystems comprise flows of energy and materials, structured by organisms and their interactions. Important generalizations have emerged in recent decades about conversions by organisms of energy (metabolic theory of ecology) and materials (ecological stoichiometry). However, these new insights leave a key question about ecosystems inadequately addressed: are there basic organizational principles that explain how the interaction structure among species in ecosystems arises? Here we integrate recent contributions to the understanding of how ecosystem organization emerges through ecological autocatalysis (EA), in which species mutually benefit through self-reinforcing circular interaction structures. We seek to generalize the concept of EA by integrating principles from community and ecosystem ecology. We discuss evidence suggesting that ecological autocatalysis is facilitated by resource competition and natural selection, both central principles in community ecology. Furthermore, we suggest that pre-emptive resource competition by consumers and plant resource diversity drive the emergence of autocatalytic loops at the ecosystem level. Subsequently, we describe how interactions between such autocatalytic loops can explain pattern and processes observed at the ecosystem scale, and summarize efforts to model different aspect of the phenomenon. We conclude that EA is a central principle that forms the backbone of the organization in systems ecology, analogous to autocatalytic loops in systems chemistry.</p