Complex Effects of a Land-Use Gradient on Pollinators and Natural Enemies: Natural Habitats Mitigate the Effects of Aphid Infestation on Pollination Services.

Pollinators and natural enemies are essential ecosystem service providers influenced by land-use and by interactions between them. However, the understanding of the combined impacts of these factors on pollinator and natural enemy activities and their ultimate effects on plant productivity remains limited. We investigated the effects of local and landscape vegetation characteristics and the presence of herbivorous pests on pollination and biological control services and their combined influence on phytometer seed set. The study was conducted in a Mediterranean agro-ecosystem, encompassing ten shrubland plots spanning a land-use gradient. Within each plot, we placed caged and uncaged potted phytometer plants that were either aphid-infested or aphid-free. We quantified insect flower visitation, aphid predation and parasitism rates, and fruit and seed set. We found scale-dependent responses of pollinators and natural enemies to land-use characteristics. Flower species richness had a positive impact on aphid parasitism rates but a negative effect on pollinator activity. Notably, we found a more pronounced positive effect of natural areas on pollinator activity in aphid-infested compared to aphid-free plants, indicating a potentially critical role of natural habitats in mitigating the adverse effects of aphid infestation on pollination services. These results highlight the complex and interactive effects of land-use on pollinators and natural enemies, with significant implications for plant productivity.

The Role of 68 Ga-FAPI PET/CT in Breast Cancer Response Assessment and Follow-Up.

PURPOSE: 68 Ga-fibroblast activation protein inhibitor (FAPI), a new PET/CT radiotracer targeting cancer-associated fibroblasts in tumor microenvironment, can detect many types of cancer. We aimed to assess whether it can also be used for response assessment and follow-up. METHODS: We followed up patients with FAPI-avid invasive lobular breast cancer (ILC) before and after treatment changes and correlated qualitative maximal intensity projection images and quantitative tumor volume with CT results and blood tumor biomarkers. RESULTS: Six consenting ILC breast cancer patients (53 ± 8 years old) underwent a total of 24 scans (baseline for each patient and 2-4 follow-up scans). We found a strong correlation between 68 Ga-FAPI tumor volume and blood biomarkers ( r = 0.7, P < 0.01), but weak correlation between CT and 68 Ga-FAPI maximal intensity projection-based qualitative response assessment. CONCLUSIONS: We found a strong correlation between ILC progression and regression (as assessed by blood biomarkers) and 68 Ga-FAPI tumor volume. 68 Ga-FAPI PET/CT could possibly be used for disease response assessment and follow-up.

The Role of 68 Ga-FAPI PET/CT in Detection of Metastatic Lobular Breast Cancer.

PURPOSE: Invasive lobular breast cancer (ILC) may be hard to detect using conventional imaging modalities and usually shows less avidity to 18 F-FDG PET/CT. 68 Ga-fibroblast activation protein inhibitor (FAPI) PET/CT has shown promising results in detecting non- 18 F-FDG-avid cancers. We aimed to assess the feasibility of detecting metastatic disease in patients with non- 18 F-FDG-avid ILC. METHODS: This prospective study included patients with metastatic ILC, infiltrative to soft tissues, which was not 18 F-FDG avid. The patients underwent 68 Ga-FAPI PET/CT for evaluation, which was correlated with the fully diagnostic CT performed at the same time. RESULTS: Seven women (aged 57 ± 10 years) were included. Among the 30 organs and structures found to be involved by tumor, the number of findings observed by FAPI PET/CT was significantly higher than that observed by CT alone ( P = 0.022), especially in infiltrative soft tissue and serosal locations. CONCLUSIONS: This small pilot trial suggests a role for 68 Ga-FAPI PET/CT in ILC, which needs to be confirmed by subsequent trials.

Rangeland sharing by cattle and bees: moderate grazing does not impair bee communities and resource availability.

Rangelands are a dominant anthropogenic land use and a main driver of natural habitat loss worldwide. Land sharing, the integration of agricultural production and biodiversity conservation, may provide a platform for managing rangelands to fulfill multiple ecosystem services. However, livestock grazing can greatly affect biodiversity and little is known about its effects on providers of focal ecosystem services, such as pollinators. We investigated the effect of cattle grazing on bee communities and their foraging and nesting resources in Mediterranean rangelands. Specifically, we explored the effect of moderate cattle grazing on flowering plant abundance, species richness and composition, the diversity of nesting substrates, and consequently, the possible effects on wild bee and honey bee foraging activity, species diversity, and community composition. We conducted field research in the Mediterranean rangelands of Israel during the main bee activity season, in the spring of 2012 and 2013, comparing paired cattle-grazed and ungrazed areas. The availability of floral and nesting resources for bees was unaffected or positively affected by grazing. Similarly, wild bee abundance, species richness, and composition were not affected by grazing, but were instead shaped by spatiotemporal factors. Nor was honey bee activity level impaired by grazing. The foraging preferences of bees, as well as flower species composition and peak bloom differed between grazed and ungrazed areas. Therefore, in our studied rangelands, grazing had its main effect on the foraging choices of honey bees and wild bees, rather than on their abundance and diversity. Moreover, our results indicate the potentially important role of ungrazed patches in increasing nectar and pollen diversity and availability in rangelands for both honey bees and wild bees in the spring. Hence, maintaining a mosaic of moderately grazed and ungrazed patches is expected to provide the greatest benefits for wild bee conservation and honey bee activity in Mediterranean rangelands. Our findings support the notion of rangeland sharing by cattle and bees in Mediterranean ecosystems under moderate grazing intensities, mimicking the coexistence of honey bees, wild bees, and cattle in Mediterranean ecosystems on an evolutionary timescale.

Validation of diagnostic gene sets to identify critically ill patients with sepsis.

PURPOSE: Gene expression diagnostics have been proposed to identify critically ill patients with sepsis. Three expression-based scores have been developed, but have not been compared in a prospective validation. We sought to validate these scores using an independent dataset and analysis. METHODS: We generated gene expression profiles from 61 critically ill patients. We validated the performance of 3 expression-based sepsis scores including 1) the Sepsis MetaScore (SMS); 2) the SeptiCyte™ Lab; and 3) the FAIM3:PLAC8 ratio. Sepsis was identified as the presence of definite, probable, or possible infection in the setting of organ dysfunction (SOFA score ≥ 2). RESULTS: For all 3 models, scores were significantly different between patients with and without sepsis. Discrimination was highest for the SMS (area under the receiver operating characteristics curve [AUROC 0.80 [95% CI 0.67-0.92]), with greater confidence in the presence of infection resulting in better model performance (max AUROC 0.93 [0.87-1.0]). CONCLUSIONS: All three scores distinguished septic from non-septic ICU patients, with the SMS showing the best performance overall in our cohort. Our results suggest that models developed from the co-analysis of multiple cohorts are more generalizable. Further work is needed to identify expression-based biomarkers of response to specific therapies.

Ribosomal Antibiotics: Contemporary Challenges.

Most ribosomal antibiotics obstruct distinct ribosomal functions. In selected cases, in addition to paralyzing vital ribosomal tasks, some ribosomal antibiotics are involved in cellular regulation. Owing to the global rapid increase in the appearance of multi-drug resistance in pathogenic bacterial strains, and to the extremely slow progress in developing new antibiotics worldwide, it seems that, in addition to the traditional attempts at improving current antibiotics and the intensive screening for additional natural compounds, this field should undergo substantial conceptual revision. Here, we highlight several contemporary issues, including challenging the common preference of broad-range antibiotics; the marginal attention to alterations in the microbiome population resulting from antibiotics usage, and the insufficient awareness of ecological and environmental aspects of antibiotics usage. We also highlight recent advances in the identification of species-specific structural motifs that may be exploited for the design and the creation of novel, environmental friendly, degradable, antibiotic types, with a better distinction between pathogens and useful bacterial species in the microbiome. Thus, these studies are leading towards the design of "pathogen-specific antibiotics," in contrast to the current preference of broad range antibiotics, partially because it requires significant efforts in speeding up the discovery of the unique species motifs as well as the clinical pathogen identification.

Crystal structure of the synergistic antibiotic pair, lankamycin and lankacidin, in complex with the large ribosomal subunit.

The structures of the large ribosomal subunit of Deinococcus radiodurans (D50S) in complex with the antibiotic lankamycin (3.2 Å) and a double antibiotic complex of lankamycin and lankacidin C (3.45 Å) have been determined, in continuation of previous crystallographic studies on lankacidin-D50S complex. These two drugs have been previously reported to inhibit ribosomal function with mild synergistic effect. Lankamycin, a member of the macrolide family, binds in a similar manner to erythromycin. However, when in complex with lankacidin, lankamycin is located so that it can form interactions with lankacidin in the adjacent ribosomal binding site. When compared to the well-documented synergistic antibiotics, Streptogramins A and B, the pair of lankacidin and lankamycin bind in similar sites, the peptidyl transferase center and nascent peptide exit tunnel, respectively. Herein, we discuss the structural basis for antibiotic synergism and highlight the key factors involved in ribosomal inhibition.

Ancient machinery embedded in the contemporary ribosome.

Structural analysis, supported by biochemical, mutagenesis and computational evidence, indicates that the peptidyltransferase centre of the contemporary ribosome is a universal symmetrical pocket composed solely of rRNA. This pocket seems to be a relic of the proto-ribosome, an ancient ribozyme, which was a dimeric RNA assembly formed from self-folded RNA chains of identical, similar or different sequences. This could have occurred spontaneously by gene duplication or gene fusion. This pocket-like entity was capable of autonomously catalysing various reactions, including peptide bond formation and non-coded or semi-coded amino acid polymerization. Efforts toward the structural definition of the early entity capable of genetic decoding involve the crystallization of the small ribosomal subunit of a bacterial organism harbouring a single functional rRNA operon.

The Proto-Ribosome: an ancient nano-machine for peptide bond formation.

The ribosome is a ribozyme whose active site, the peptidyl transferase center (PTC) is situated within a highly conserved universal symmetrical region that connects all ribosomal functional centers involved in amino-acid polymerization. The linkage between this elaborate architecture and A-site tRNA position revealed that the A to P-site passage of the tRNA 3' terminus during protein synthesis is performed by a rotary motion, synchronized with the overall tRNA/mRNA sideways movement and Guided by the PTC. This rotary motion leads to suitable stereochemistry for peptide bond formation as well as for substrate mediated catalysis. Analysis of the substrate binding modes to ribosomes led to the hypothesis that the ancient ribosome produced single peptide bonds and non-coded chains, potentially in a similar manner to the modern PTC. Later in evolution, a mechanism, enabling some type of decoding genetic control triggered the emergence of the small ribosomal subunit or part of it. This seems to be the result of the appearance of reaction products that could have evolved after polypeptides capable of enzymatic function were generated sporadically, while an ancient stable RNA fold was converted into an old version of a tRNA molecule. As in the contemporary ribosome the symmetry relates only the backbone fold and nucleotides orientations but not nucleotide sequences, it emphasizes the superiority of functional requirement over sequence conservation, and indicates that the PTC may have evolved by gene fusion or gene duplication.

Analysis of BRCA1/BRCA2 genes' contribution to breast cancer susceptibility in high risk Jewish Ashkenazi women.

BACKGROUND: Three mutations in BRCA1 (185delAG 5382InsC) and BRCA2 (6174delT) can be detected in a substantial proportion of Jewish Ashkenazi breast/ovarian cancer families. Family-specific pathogenic mutations in both genes can be detected in up to 5% of high risk Ashkenazim. The contribution of major gene rearrangements and seemingly pathogenic missense mutations to inherited breast cancer predisposition has never been systematically evaluated in Ashkenazim. MATERIAL AND METHODS: High risk, Jewish Ashkenazi women, non-carriers of the predominant Jewish BRCA1/BRCA2 mutations, were genotyped for major gene rearrangements in BRCA1/BRCA2 using Multiplex ligation-dependent probe amplification (MLPA), and for the occurrence rate of 6 seemingly pathogenic missense mutations in BRCA1 (R866C, R331S, R841W, Y179C, C61G, M1008I) using a modified restriction enzyme assay. RESULTS: Overall, 105 Jewish Ashkenazi high risk women, participated in the study: 104 with breast cancer [age at diagnosis (mean +/- SD) 51.05 +/- 11.13 years], one was affected with ovarian cancer (61 years). Two were found to carry the M1008I mutation in BRCA1 and none harbored any of the other missense mutations. MLPA reveled four changes (amplifications of exons 5, 17, 19 and 21) in BRCA1 in five patients, and six patients exhibited 4 MLPA-detectable abnormalities in BRCA2 (amplifications in exons 1b, 2, and deletions in exons 11a and 25). None of these abnormalities could be confirmed using quantitative PCR (qPCR) analysis. CONCLUSIONS: Major gene rearrangements involving BRCA1 BRCA2 contribute little to the burden of inherited predisposition of breast cancer in Ashkenazi Jews.

How I treat acute and chronic leukemia in pregnancy.

The prevalence of pregnancy associated leukemia is approximately 1 case out of 10,000 pregnancies. This rare occurrence precludes the conducting of large, prospective studies to examine diagnostic, management and outcome issues. The treatment of a pregnant woman with leukemia may be associated with severe adverse fetal outcome including death and malformations, and therefore poses a difficult challenge for both the patient and the attending physician. Chemotherapy during the 1st trimester is associated with an increased risk for congenital malformations. However, this risk diminishes as pregnancy advances. When acute leukemia is diagnosed during the 1st trimester, patients should be treated promptly similar to non-pregnant patients. However, the aggressive induction therapy should follow pregnancy termination. When the diagnosis is made later in pregnancy standard chemotherapy regimen should be considered and usually pregnancy termination is not mandatory. However, both the mother and the fetus should be under close observation and delivery should be postponed to a non-cytopenic period. Pregnancy associated chronic myelogenous leukemia (CML) can be treated with interferon throughout pregnancy with no apparent increase in adverse fetal outcome. In the very rare case of chronic lymphocytic leukemia (CLL) during pregnancy treatment can usually be delayed until after delivery.