An unbiased approach elucidates variation in (S)-(+)-linalool, a context-specific mediator of a tri-trophic interaction in wild tobacco

Plant volatile organic compounds (VOCs) mediate many interactions, and the function of common VOCs is especially likely to depend on ecological context. We used a genetic mapping population of wild tobacco, Nicotiana attenuata, originating from a cross of 2 natural accessions from Arizona and Utah, separated by the Grand Canyon, to dissect genetic variation controlling VOCs. Herbivory-induced leaf terpenoid emissions varied substantially, while green leaf volatile emissions were similar. In a field experiment, only emissions of linalool, a common VOC, correlated significantly with predation of the herbivore Manduca sexta by native predators. Using quantitative trait locus mapping and genome mining,we identified an (S)-(+)-linalool synthase (NaLIS). Genome resequencing, gene cloning, and activity assays revealed that the presence/absence of a 766-bp sequence in NaLIS underlies the variation of linalool emissions in 26 natural accessions. We manipulated linalool emissions and composition by ectopically expressing linalool synthases for both enantiomers, (S)-(+)- and (R)-(−)-linalool, reported to oppositely affect M. sexta oviposition, in the Arizona and Utah accessions.We used these lines to test ovipositingmoths in increasingly complex environments. The enantiomers had opposite effects on oviposition preference, but themagnitude of the effect depended strongly both on plant genetic background, and complexity of the bioassay environment. Our study reveals that the emission of linalool, a common VOC, differs by orders-of-magnitude among geographically interspersed conspecific plants due to allelic variation in a linalool synthase, and that the response of a specialist herbivore to linalool depends on enantiomer, plant genotype, and environmental complexity

Lipidomics signature in post-COVID patient sera and its influence on the prolonged inflammatory response

Background: The ongoing issues with post-COVID conditions (PCC), where symptoms persist long after the initial infection, highlight the need for research into blood lipid changes in these patients. While most studies focus on the acute phase of COVID-19, there's a significant lack of information on the lipidomic changes that occur in the later stages of the disease. Addressing this knowledge gap is critical for understanding the long-term effects of COVID-19 and could be key to developing personalized treatments for those suffering from PCC. Methods: We employed untargeted lipidomics to analyze plasma samples from 147 PCC patients, assessing nearly 400 polar lipids. Data mining (DM) and machine learning (ML) tools were utilized to decode the results and ascertain significant lipidomic patterns. Results: The study uncovered substantial changes in various lipid subclasses, presenting a detailed profile of the polar lipid fraction in PCC patients. These alterations correlated with ongoing inflammation and immune response. Notably, there were elevated levels of lysophosphatidylglycerols (LPGs) and phosphatidylethanolamines (PEs), and reduced levels of lysophosphatidylcholines (LPCs), suggesting these as potential lipid biomarkers for PCC. The lipidomic signatures indicated specific anionic lipid changes, implicating antimicrobial peptides (AMPs) in inflammation. Associations between particular medications and symptoms were also suggested. Classification models, such as multinomial regression (MR) and random forest (RF), successfully differentiated between symptomatic and asymptomatic PCC groups using lipidomic profiles. Conclusions: The study's groundbreaking discovery of specific lipidomic disruptions in PCC patients marks a significant stride in the quest to comprehend and combat this condition. The identified lipid biomarkers not only pave the way for novel diagnostic tools but also hold the promise to tailor individualized therapeutic strategies, potentially revolutionizing the clinical approach to managing PCC and improving patient care

The olfactory coreceptor IR8a governs larval feces-mediated competition avoidance in a hawkmoth

Finding a suitable oviposition site is a challenging task for a gravid female moth. At the same time, it is of paramount importance considering the limited capability of most caterpillars to relocate to alternative host plants. The hawkmoth, Manduca sexta, oviposits on solanaceous plants. Larvae hatching on a plant that is already attacked by conspecific caterpillars face food competition. Here, we show that feces from conspecific caterpillars are sufficient to deter a female M. sexta from ovipositing on a plant. Furthermore, we not only identify the responsible compound in the feces but also localize the population of sensory neurons that governs the female’s avoidance. Hence, our work increases the understanding of how animals cope with a competitive environment

Coexistence of Two Rare Sarcomas: Primary Leiomyosarcoma of Bone and Epithelioid Hemangioendothelioma of the Liver

A 33-year-old woman sought medical attention for a painful swelling of the left ankle. Plain radiographs revealed an osteolytic lesion involving the left distal tibia. An excisional biopsy provided the diagnosis of leiomyosarcoma in the tibia. A staging work-up was performed and an abdominal CT showed 4 liver hypodense lesions in both lobes with peripheral contrast enhancement. A liver biopsy confirmed the diagnosis of epithelioid hemangioendothelioma of the liver. No association between these two entities has been described before. This case introduces the importance of the pathological confirmation of apparent metastatic lesions in low grade sarcomas and provides a review of the literature of both tumours

Prevention of delayed cerebral vasospasm by continuous intrathecal infusion of glyceroltrinitrate and nimodipine in the rabbit model in vivo

OBJECTIVE: Intrathecal bolus administration of nitric oxide donors and calcium channel antagonists has been proposed to reduce cerebral vasospasm (CVS) in animal subarachnoid hemorrhage (SAH) models. Intrathecal continuous administration of these substances for CVS prevention has not been extensively evaluated. This study compared the efficacy of continuous intrathecal infusions of the NO donor glyceroltrinitrate and nimodipine in preventing delayed CVS associated with SAH in an animal model in vivo. METHODS: New Zealand White rabbits were randomly assigned to six groups: no SAH/NaCl, no SAH/NO, no SAH/nimodipine, SAH/NaCl, SAH/NO, or SAH/nimodipine. Glyceroltrinitrate (GTN) at 0.5 microg/microl (0.5 microl/h) or nimodipine at 0.2 microg/microl (10 microl/h) or NaCl was continuously infused into the cisterna magna via an Alzet osmotic pump from day 0 to day 5 after injection of 1.0 ml autologous blood. The magnitude of spasm in the basilar artery was determined by comparison of pre- and posttreatment angiography and was calculated as proportional change in intraluminal diameter based on automatic measurements. RESULTS: A total of 55 experiments and 110 angiograms were performed. SAH was associated with vasoconstriction of the basilar artery (SAH/NaCl group 19.85+/-2.94%). Continuous intrathecal injection of GTN and nimodipine prevented SAH-induced CVS. There was significant prevention of CVS in animals treated with GTN (SAH/NO group 5.93+/-5.2%, n=11) and nimodipine (SAH/nimodipine group: 0.55+/-2.66%, n=9). There was no significant difference between the treatment groups and controls in prevention of CVS. CONCLUSIONS: This study demonstrates that prophylactic continuous intrathecal administration of either GTN or nimodipine equally prevents SAH-associated CVS in an animal model

FGFR1 amplification or overexpression and hormonal resistance in luminal breast cancer: rationale for a triple blockade of ER, CDK4/6, and FGFR1.

BACKGROUND: FGFR1 amplification, but not overexpression, has been related to adverse prognosis in hormone-positive breast cancer (HRPBC). Whether FGFR1 overexpression and amplification are correlated, what is their distribution among luminal A or B HRPBC, and if there is a potential different prognostic role for amplification and overexpression are currently unknown features. The role of FGFR1 inhibitors in HRPBC is also unclear. METHODS: FGFR1 amplification (FISH) and overexpression (RNAscope) were investigated in a N = 251 HRPBC patients cohort and the METABRIC cohort; effects on survival and FISH-RNAscope concordance were determined. We generated hormonal deprivation resistant (LTED-R) and FGFR1-overexpressing cell line variants of the ER+ MCF7 and T47-D and the ER+, FGFR1-amplified HCC1428 cell lines. The role of ER, CDK4/6, and/or FGFR1 blockade alone or in combinations in Rb phosphorylation, cell cycle, and survival were studied. RESULTS: FGFR1 overexpression and amplification was non-concordant in > 20% of the patients, but both were associated to a similar relapse risk (~ 2.5-fold; P < 0.05). FGFR1 amplification or overexpression occurred regardless of the luminal subtype, but the incidence was higher in luminal B (16.3%) than A (6.6%) tumors; P < 0.05. The Kappa index for overexpression and amplification was 0.69 (P < 0.001). Twenty-four per cent of the patients showed either amplification and/or overexpression of FGFR1, what was associated to a hazard ratio for relapse of 2.6 (95% CI 1.44-4.62, P < 0.001). In vitro, hormonal deprivation led to FGFR1 overexpression. Primary FGFR1 amplification, engineered mRNA overexpression, or LTED-R-acquired FGFR1 overexpression led to resistance against hormonotherapy alone or in combination with the CDK4/6 inhibitor palbociclib. Blocking FGFR1 with the kinase-inhibitor rogaratinib led to suppression of Rb phosphorylation, abrogation of the cell cycle, and resistance-reversion in all FGFR1 models. CONCLUSIONS: FGFR1 amplification and overexpression are associated to similar adverse prognosis in hormone-positive breast cancer. Capturing all the patients with adverse prognosis-linked FGFR1 aberrations requires assessing both features. Hormonal deprivation leads to FGFR1 overexpression, and FGFR1 overexpression and/or amplification are associated with resistance to hormonal monotherapy or in combination with palbociclib. Both resistances are reverted with triple ER, CDK4/6, and FGFR1 blockade

Analysis of Paired Primary-Metastatic Hormone-Receptor Positive Breast Tumors (HRPBC) Uncovers Potential Novel Drivers of Hormonal Resistance

We sought to identify genetic variants associated with disease relapse and failure to hormonal treatment in hormone-receptor positive breast cancer (HRPBC). We analyzed a series of HRPBC with distant relapse, by sequencing pairs (n = 11) of tumors (primary and metastases) at >800X. Comparative genomic hybridization was performed as well. Top hits, based on the frequency of alteration and severity of the changes, were tested in the TCGA series. Genes determining the most parsimonious prognostic signature were studied for their functional role in vitro, by performing cell growth assays in hormonal-deprivation conditions, a setting that mimics treatment with aromatase inhibitors. Severe alterations were recurrently found in 18 genes in the pairs. However, only MYC, DNAH5, CSFR1, EPHA7, ARID1B, and KMT2C preserved an independent prognosis impact and/or showed a significantly different incidence of alterations between relapsed and non-relapsed cases in the TCGA series. The signature composed of MYC, KMT2C, and EPHA7 best discriminated the clinical course, (overall survival 90,7 vs. 144,5 months; p = 0.0001). Having an alteration in any of the genes of the signature implied a hazard ratio of death of 3.25 (p<0.0001), and early relapse during the adjuvant hormonal treatment. The presence of the D348N mutation in KMT2C and/or the T666I mutation in the kinase domain of EPHA7 conferred hormonal resistance in vitro. Novel inactivating mutations in KMT2C and EPHA7, which confer hormonal resistance, are linked to adverse clinical course in HRPBC

Competing beetles attract egg laying in a hawkmoth

In nature, plant-insect interactions occur in complex settings involving multiple trophic levels, often with multiple species at each level.1 Herbivore attack of a host plant typically dramatically alters the plant’s odor emission in terms of concentration and composition.2,3 Therefore, a well-adapted herbivore should be able to predict whether a plant is still suitable as a host by judging these changes in the emitted bouquet. Although studies have demonstrated that oviposition preferences of successive insects were affected by previous infestations,4,5 the underlying molecular and olfactory mechanisms remain unknown. Here, we report that tobacco hawkmoths (Manduca sexta) preferentially oviposit on Jimson weed (Datura wrightii) that is already infested by a specialist, the three-lined potato beetle (Lema daturaphila). Interestingly, the moths’ offspring do not benefit directly, as larvae develop more slowly when feeding together with Lema beetles. However, one of M. sexta’s main enemies, the parasitoid wasp Cotesia congregata, prefers the headspace of M. sexta-infested plants to that of plants infested by both herbivores. Hence, we conclude that female M. sexta ignore the interspecific competition with beetles and oviposit deliberately on beetle-infested plants to provide their offspring with an enemy-reduced space, thus providing a trade-off that generates a net benefit to the survival and fitness of the subsequent generation. We identify that α-copaene, emitted by beetle-infested Datura, plays a role in this preference. By performing heterologous expression and single-sensillum recordings, we show that odorant receptor (Or35) is involved in α-copaene detection.Publikationsfonds ML