Determinants of female fecundity in a simultaneous hermaphrodite: the role of polyandry and food availability

Classical sexual selection theory assumes that the reproductive success of females is primarily limited by the resources available for egg production rather than by the number of mating partners. However, there is now accumulating evidence that multiple mating can entail fitness costs or benefits for females. In this study we investigated the effect of polyandry (i.e., the mating with different mating partners) and food availability on the reproductive output of the female sex function in an outcrossing simultaneous hermaphrodite, the free-living flatworm Macrostomum lignano. We exposed virgin worms to different group sizes, a treatment that has previously been shown to affect the level of polyandry in this species. Moreover, we manipulated the food availability throughout the subsequent egg laying period, during which the worms were kept in isolation. The number of offspring produced was used as an estimate of female fecundity. We found that food availability, but not group size, had a significant effect on female fecundity. Additionally, female fecundity was positively correlated with the number of stored sperm in the female sperm-storage organ at the time of isolation, but it was not correlated with body or ovary size of the worms. Our results suggest that female fecundity in M.lignano is primarily determined by the resources available for egg production, and not by the level of polyandry, confirming classic sexual selection theory for simultaneous hermaphrodite

mTORC2 critically regulates renal potassium handling

The mTOR pathway orchestrates cellular homeostasis. The rapamycin-sensitive mTOR complex (mTORC1) in the kidney has been widely studied; however, mTORC2 function in renal tubules is poorly characterized. Here, we generated mice lacking mTORC2 in the distal tubule (Rictorfl/fl Ksp-Cre mice), which were viable and had no obvious phenotype, except for a 2.5-fold increase in plasma aldosterone. Challenged with a low-Na+ diet, these mice adequately reduced Na+ excretion; however, Rictorfl/fl Ksp-Cre mice rapidly developed hyperkalemia on a high-K+ diet, despite a 10-fold increase in serum aldosterone levels, implying that mTORC2 regulates kaliuresis. Phosphorylation of serum- and glucocorticoid-inducible kinase 1 (SGK1) and PKC-α was absent in Rictorfl/fl Ksp-Cre mice, indicating a functional block in K+ secretion activation via ROMK channels. Indeed, patch-clamp experiments on split-open tubular segments from the transition zone of the late connecting tubule and early cortical collecting duct demonstrated that Ba2+-sensitive apical K+ currents were barely detectable in the majority of Rictorfl/fl Ksp-Cre mice. Conversely, epithelial sodium channel (ENaC) activity was largely preserved, suggesting that the reduced ability to maintain K+ homeostasis is the result of impaired apical K+ conductance and not a reduced electrical driving force for K+ secretion. Thus, these data unravel a vital and nonredundant role of mTORC2 for distal tubular K+ handling

Effect of confinement on the characterization of nanoporous materials by NMR relaxometry

Valid textural characterization is crucial for many applications such as catalysis, separation as well as energy storage/conversion. In that regard, textural characterization in the gas/dry state using gas physisorption and mercury porosimetry is well established, but these methods might not be sufficient for the characterization of wet materials used in liquid-phase processes. Within this context, the applicability of nuclear magnetic resonance (NMR) relaxometry for surface area assessment of nonporous silica/carbon materials has been demonstrated [Schlumberger et al. (2023). https://doi.org/10.1021/acs.langmuir.2c03337 ]. However, a comprehensive and rigorous assessment of the applicability of NMR relaxometry for surface area and pore size assessment of nanoporous materials coupled with a systematic investigation of how the confinement affects the NMR relaxation behavior is missing so far. Hence, we present here a systematic study based on a series of ordered mesoporous silica model materials exhibiting well-defined pore sizes between approx. 2.5 and 10 nm saturated with a bulk liquid water as well as a bulk water vapor phase. The study suggests that an adaption of the two-fraction-fast-exchange model to account for the pore geometry is necessary for valid surface area assessment as well as pore size analysis of nanoporous silica material particularly for pores smaller than approx. 10 nm.Open Access funding enabled and organized by Projekt DEAL.Friedrich-Alexander-Universität Erlangen-Nürnberg (1041

P2Y2R Signaling Is Involved in the Onset of Glomerulonephritis

Endogenously released adenosine-5’-triphosphate (ATP) is a key regulator of physiological function and inflammatory responses in the kidney. Genetic or pharmacological inhibition of purinergic receptors has been linked to attenuation of inflammatory disorders and hence constitutes promising new avenues for halting and reverting inflammatory renal diseases. However, the involvement of purinergic receptors in glomerulonephritis (GN) has only been incompletely mapped. Here, we demonstrate that induction of GN in an experimental antibody-mediated GN model results in a significant increase of urinary ATP-levels and an upregulation of P2Y2R expression in resident kidney cells as well as infiltrating leukocytes pointing toward a possible role of the ATP/P2Y2R-axis in glomerular disease initiation. In agreement, decreasing extracellular ATP-levels or inhibition of P2R during induction of antibody-mediated GN leads to a reduction in all cardinal features of GN such as proteinuria, glomerulosclerosis, and renal failure. The specific involvement of P2Y2R could be further substantiated by demonstrating the protective effect of the lack of P2Y2R in antibody-mediated GN. To systematically differentiate between the function of P2Y2R on resident renal cells versus infiltrating leukocytes, we performed bone marrow-chimera experiments revealing that P2Y2R on hematopoietic cells is the main driver of the ATP/P2Y2R-mediated disease progression in antibody-mediated GN. Thus, these data unravel an important pro-inflammatory role for P2Y2R in the pathogenesis of GN

Early kinetics of C reactive protein for cancer-agnostic prediction of therapy response and mortality in patients treated with immune checkpoint inhibitors: a multicenter cohort study

Background C reactive protein (CRP) kinetics have recently been suggested as predictive biomarkers for the efficacy of immune checkpoint inhibitor (ICI) therapy in selected cancer types. The aim of this study was to characterize early CRP kinetics as a tumor-agnostic biomarker for ICI treatment outcomes.Methods In this multicenter retrospective cohort study, two independent cohorts of patients with various cancer types undergoing palliative ICI treatment at Austrian academic centers served as the discovery (n=562) and validation cohort (n=474). Four different patterns of CRP kinetics in the first 3 months of ICI therapy were defined (CRP-flare responders, CRP-responders, CRP non-responders, patients with all-normal CRP). Objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) were defined as coprimary endpoints. Univariable and multivariable logistic regression, landmark analysis and Cox regression including CRP kinetics as time-dependent variable were performed.Results The ORR in patients with all-normal CRP, CRP responders, CRP flare-responders and CRP non-responders was 41%, 38%, 31% and 12%, respectively. The median OS and PFS estimates were 24.5 months (95% CI 18.5 to not reached) and 8.2 months (95% CI 5.9 to 12.0) in patients with all-normal CRP, 16.1 months (95% CI 12.6 to 19-8) and 6.1 months (95% CI 4.9 to 7.2) in CRP-responders, 14.0 months (95% CI 8.5 to 19.4) and 5.7 months (95% CI 4.1 to 8.5) in CRP flare-responders and 8.1 months (95% CI 5.8 to 9.9) and 2.3 months (95% CI 2.2 to 2.8) in CRP non-responders (log-rank p for PFS and OS<0.001). These findings prevailed in multivariable analysis and could be fully confirmed in our validation cohort. Pooled subgroup analysis suggested a consistent predictive significance of early CRP kinetics for treatment efficacy and outcome independent of cancer type.Conclusion Early CRP kinetics represent a tumor-agnostic predictor for treatment response, progression risk and mortality in patients with cancer undergoing ICI therapy

Abstracts from the 8th International Conference on cGMP Generators, Effectors and Therapeutic Implications

This work was supported by a restricted research grant of Bayer AG

Mating behaviour of the marine turbellarian Macrostomum sp. : these worms; suck

Simultaneous hermaphrodites experience unique conflicts of interest during reproduction, some of which are reflected in their complex mating behaviours. We here provide the first detailed description of the mating behaviour of a marine flatworm of the genus Macrostomum, a cosmopolitan group of microturbellaria. Mating in this species is usually initiated by the precopulatory behaviours circling and reeling, then leads to reciprocal copulation where worms mutually insert their copulatory stylet, and often ends in an intriguing postcopulatory sucking behaviour. We provide detailed data on the frequencies and durations of the different behaviours, and examine some biotic and abiotic factors that could influence the mating rate. We further speculate on the function of sucking and suggest that it could be an adaptation for the digestion of sperm and/or the removal of seminal components, which may function as allohormones

Multimodale pharmakologische Therapieinterventionen bei einem Mausmodell für polyzystische Nierenerkrankungen

Für Patienten mit einer polyzystischen Nierenerkrankung gibt es trotz intensiverForschung bis heute keine pharmakologischen Therapiemöglichkeiten. Da beidieser Erkrankung die Aktivität des Proteins mTORC1 pathologisch erhöht ist, sindanti-proliferativ wirksame mTORC1-Inhibitoren große Favoriten für einekonservative pharmakologische Therapie. In zwei Patientenstudien mit denmTORC1-Inhibitoren Everolimus und Sirolimus konnte jedoch die Nierenfunktionbeim Menschen nicht verbessert werden. Deshalb war es das Ziel dieser Doktorarbeit, die Wirkung von Everolimus ineinem Mausmodell für die polyzystische Nierenerkrankung weiter zu erforschen. DieUntersuchungen wurden durch die proliferationshemmenden SubstanzenNVP-BEZ235, Nutlin-3a und ein durch Roscovitin-Analogon ergänzt. In den detaillierten funktionellen, biochemischen und histologischenUntersuchungen der Niere konnte eine Verbesserung der Nierenfunktion und eineInhibition von Signalwegen, die für das Zystenwachstum entscheidend sind, gezeigtwerden. Interessanterweise wurde im Spätstadium der Erkrankung dieanti-proliferative Wirkung von Everolimus durch die Aktivierung vonmTORC1-unabhängigen Signalwegen kompensiert. Außerdem zeigen die Daten,dass eine Proliferationshemmung vor allem in einem frühen Stadium derErkrankung von Vorteil war. Zusätzlich legt diese Arbeit nahe, dass die verspäteteAnwendung von anti-proliferativ wirkenden Substanzen die natürliche Regenerationdes Nierengewebes hemmen könnte. Da Everolimus in der Patientenstudie von Walz et al. in einem bereitsfortgeschrittenen Krankheitsstadium gegeben wurde, korreliert dasTherapieversagen mit den Beobachtungen in dieser Doktorarbeit. Gleichzeitigwurde aufgezeigt, dass eine Proliferationshemmung bei Patienten mit einerpolyzystischen Nierenerkrankung in einem frühen Stadium eine Therapiemöglichkeitdarstellen könnte