mTORC1 in the Paneth cell niche couples intestinal stem-cell function to calorie intake

How adult tissue stem and niche cells respond to the nutritional state of an organism is not well understood. Here we find that Paneth cells, a key constituent of the mammalian intestinal stem-cell (ISC) niche, augment stem-cell function in response to calorie restriction. Calorie restriction acts by reducing mechanistic target of rapamycin complex 1 (mTORC1) signalling in Paneth cells, and the ISC-enhancing effects of calorie restriction can be mimicked by rapamycin. Calorie intake regulates mTORC1 in Paneth cells, but not ISCs, and forced activation of mTORC1 in Paneth cells during calorie restriction abolishes the ISC-augmenting effects of the niche. Finally, increased expression of bone stromal antigen 1 (Bst1) in Paneth cells—an ectoenzyme that produces the paracrine factor cyclic ADP ribose—mediates the effects of calorie restriction and rapamycin on ISC function. Our findings establish that mTORC1 non-cell-autonomously regulates stem-cell self-renewal, and highlight a significant role of the mammalian intestinal niche in coupling stem-cell function to organismal physiology.     

The Duhem-Quine problem for equiprobable conjuncts

In this paper, we distinguish Quine’s thesis of holism from the related Duhem-Quine problem. We discuss the construal of holism which claims that the effect of falsification is felt on a conjunction of hypotheses. The Duhem-Quine problem claims that there is no principled way of knowing how falsification affects individual conjuncts. This latter claim relies on holism and an additional commitment to the hypothetico-deductive model of theory confirmation such that it need not arise in non-deductive accounts. While existing personalist Bayesian treatments of the problem make this point by assuming values of priors for the conjuncts, we arrive at the same conclusion without invoking such assumptions. Our discussion focuses on the falsification of equiprobable conjuncts and highlights the role played by their alternatives in ascertaining their relative disconfirmation. The equiprobability of conjuncts is discussed alongside a historical case study     

Cytotoxicity of ethyl methanesulfonate in mice spermatogonia

Summary Enumeration of different types of spermatogonia, following a single i.p. administration of different doses of ethyl methanesulfonate in mice, showed that survival of A₁–A₄ and in spermatogonia is markedly reduced due to cell killing while the remaining types of spermatogonia were affected marginally. The cell killing effect was dose-dependent, and replenishment of these cells was observed by the end of one cycle of the seminiferous epithelium comprising of 8.5 days.     

Dendritic cell PAR1-S1P3 signalling couples coagulation and inflammation

Defining critical points of modulation across heterogeneous clinical syndromes may provide insight into new therapeutic approaches. Coagulation initiated by the cytokine-receptor family member known as tissue factor is a hallmark of systemic inflammatory response syndromes in bacterial sepsis and viral haemorrhagic fevers, and anticoagulants can be effective in severe sepsis with disseminated intravascular coagulation. The precise mechanism coupling coagulation and inflammation remains unresolved. Here we show that protease-activated receptor 1 (PAR1) signalling sustains a lethal inflammatory response that can be interrupted by inhibition of either thrombin or PAR1 signalling. The sphingosine 1-phosphate (S1P) axis is a downstream component of PAR1 signalling, and by combining chemical and genetic probes for S1P receptor 3 (S1P3) we show a critical role for dendritic cell PAR1-S1P3 cross-talk in regulating amplification of inflammation in sepsis syndrome. Conversely, dendritic cells sustain escalated systemic coagulation and are the primary hub at which coagulation and inflammation intersect within the lymphatic compartment. Loss of dendritic cell PAR1-S1P3 signalling sequesters dendritic cells and inflammation into draining lymph nodes, and attenuates dissemination of interleukin-1beta to the lungs. Thus, activation of dendritic cells by coagulation in the lymphatics emerges as a previously unknown mechanism that promotes systemic inflammation and lethality in decompensated innate immune responses.     

Stochastic synchronization of circadian rhythms

Models of circadian genetic oscillators involving interlinked feedback processes in molecular level genetic networks in Drosophila melanogaster and Neurospora crassa are studied, and mechanisms whereby synchronization can arise in an assembly of cells are examined. The individual subcellular circadian oscillatory processes are stochastic in nature due to the small numbers of molecules that are involved, and are subject to large fluctuations. The authors investigate and present the simulations of the stochastic dynamics of ensembles of clock-regulating proteins in different nuclei that communicate via ancillary small molecules, environmental parameters, additive cellular noise, or through diffusive processes. The results show that the emergence of collective oscillations is a macroscopic observable which has its origins in the microscopic coupling between distinct cellular oscillators.     

Paternal inheritance of a female moth's mating preference

Females of the arctiid moth Utetheisa ornatrix mate preferentially with larger males, receiving both direct phenotypic and indirect genetic benefits. Here we demonstrate that the female's mating preference is inherited through the father rather than the mother, indicating that the preference gene or genes lie mostly or exclusively on the Z sex chromosome, which is strictly paternally inherited by daughters. Furthermore, we show that the preferred male trait and the female preference for that trait are correlated, as females with larger fathers have a stronger preference for larger males. These findings are predicted by the protected invasion theory, which asserts that male homogametic sex chromosome systems (ZZ/ZW) found in lepidopterans and birds promote the evolution of exaggerated male traits through sexual selection. Specifically, the theory predicts that, because female preference alleles arising on the Z chromosome are transmitted to all sons that have the father's attractive trait rather than to only a fraction of the sons, such alleles will experience stronger positive selection and be less vulnerable to chance loss than would autosomal alleles.