Metabolic regulation of proteome stability via N-terminal acetylation controls male germline stem cell differentiation and reproduction.

The molecular mechanisms connecting cellular metabolism with differentiation remain poorly understood. Here, we find that metabolic signals contribute to stem cell differentiation and germline homeostasis during Drosophila melanogaster spermatogenesis. We discovered that external citrate, originating outside the gonad, fuels the production of Acetyl-coenzyme A by germline ATP-citrate lyase (dACLY). We show that this pathway is essential during the final spermatogenic stages, where a high Acetyl-coenzyme A level promotes NatB-dependent N-terminal protein acetylation. Using genetic and biochemical experiments, we establish that N-terminal acetylation shields key target proteins, essential for spermatid differentiation, from proteasomal degradation by the ubiquitin ligase dUBR1. Our work uncovers crosstalk between metabolism and proteome stability that is mediated via protein post-translational modification. We propose that this system coordinates the metabolic state of the organism with gamete production. More broadly, modulation of proteome turnover by circulating metabolites may be a conserved regulatory mechanism to control cell functions.

Y chromosome toxicity does not contribute to sex-specific differences in longevity.

While sex chromosomes carry sex-determining genes, they also often differ from autosomes in size and composition, consisting mainly of silenced heterochromatic repetitive DNA. Even though Y chromosomes show structural heteromorphism, the functional significance of such differences remains elusive. Correlative studies suggest that the amount of Y chromosome heterochromatin might be responsible for several male-specific traits, including sex-specific differences in longevity observed across a wide spectrum of species, including humans. However, experimental models to test this hypothesis have been lacking. Here we use the Drosophila melanogaster Y chromosome to investigate the relevance of sex chromosome heterochromatin in somatic organs in vivo. Using CRISPR-Cas9, we generated a library of Y chromosomes with variable levels of heterochromatin. We show that these different Y chromosomes can disrupt gene silencing in trans, on other chromosomes, by sequestering core components of the heterochromatin machinery. This effect is positively correlated to the level of Y heterochromatin. However, we also find that the ability of the Y chromosome to affect genome-wide heterochromatin does not generate physiological sex differences, including sexual dimorphism in longevity. Instead, we discovered that it is the phenotypic sex, female or male, that controls sex-specific differences in lifespan, rather than the presence of a Y chromosome. Altogether, our findings dismiss the 'toxic Y' hypothesis that postulates that the Y chromosome leads to reduced lifespan in XY individuals.

Engineering an NADPH/NADP+ Redox Biosensor in Yeast.

Genetically encoded biosensors have emerged as powerful tools for timely and precise in vivo evaluation of cellular metabolism. In particular, biosensors that can couple intercellular cues with downstream signaling responses are currently attracting major attention within health science and biotechnology. Still, there is a need for bioprospecting and engineering of more biosensors to enable real-time monitoring of specific cellular states and controlling downstream actuation. In this study, we report the engineering and application of a transcription factor-based NADPH/NADP+ redox biosensor in the budding yeast Saccharomyces cerevisiae. Using the biosensor, we are able to monitor the cause of oxidative stress by chemical induction, and changes in NADPH/NADP+ ratios caused by genetic manipulations. Because of the regulatory potential of the biosensor, we also show that the biosensor can actuate upon NADPH deficiency by activation of NADPH regeneration. Finally, we couple the biosensor with an expression of dosage-sensitive genes (DSGs) and thereby create a novel tunable sensor-selector useful for synthetic selection of cells with higher NADPH/NADP+ ratios from mixed cell populations. We show that the combination of exploitation and rational engineering of native signaling components is applicable for diagnosis, regulation, and selection of cellular redox states.

High-throughput screening of tick-borne pathogens in Europe.

Due to increased travel, climatic, and environmental changes, the incidence of tick-borne disease in both humans and animals is increasing throughout Europe. Therefore, extended surveillance tools are desirable. To accurately screen tick-borne pathogens (TBPs), a large scale epidemiological study was conducted on 7050 Ixodes ricinus nymphs collected from France, Denmark, and the Netherlands using a powerful new high-throughput approach. This advanced methodology permitted the simultaneous detection of 25 bacterial, and 12 parasitic species (including; Borrelia, Anaplasma, Ehrlichia, Rickettsia, Bartonella, Candidatus Neoehrlichia, Coxiella, Francisella, Babesia, and Theileria genus) across 94 samples. We successfully determined the prevalence of expected (Borrelia burgdorferi sensu lato, Anaplasma phagocytophilum, Rickettsia helvetica, Candidatus Neoehrlichia mikurensis, Babesia divergens, Babesia venatorum), unexpected (Borrelia miyamotoi), and rare (Bartonella henselae) pathogens in the three European countries. Moreover we detected Borrelia spielmanii, Borrelia miyamotoi, Babesia divergens, and Babesia venatorum for the first time in Danish ticks. This surveillance method represents a major improvement in epidemiological studies, able to facilitate comprehensive testing of TBPs, and which can also be customized to monitor emerging diseases.

Drugs targeting 5-hydroxytryptamine receptors in acute treatments of migraine attacks. A review of new drugs and new administration forms of established drugs.

INTRODUCTION: The development of sumatriptan, more than 20 years ago, added substantially to the characterization of 5-hydroxytryptamine (5-HT) receptors and their relevance to acute migraine therapy. Recently, 5-HT1F receptor agonists, with no vascular effects, have shown efficacy in the treatment of migraines. AREAS COVERED: This evaluation reviews the recent advances in acute migraine therapy targeting the 5-HT receptor. Specifically, the authors review the pharmacokinetics, pharmacodynamics, clinical efficacy and safety of 5-HT1F receptor agonists and new formulations of sumatriptan and dihydroergotamine (DHE). EXPERT OPINION: Lasmiditan, a non-vascular acting 5-HT1F receptor agonist, is effective in migraine but causes central nervous system-related adverse events, which may considerably limit its clinical use. The efficacy of transdermal sumatriptan is too low for general use in migraine. Intranasal sumatriptan powder could be a step forward compared with oral sumatriptan, but comparative trials are needed. Orally inhaled DHE has a very quick systemic absorption but the onset of effect in migraine is relatively slow with a maximum effect after 2 h. In contrast, orally inhaled DHE results in a low incidence of recurrence. None of these reviewed treatments are likely to fulfill patients' expectations, and the advancement of acute migraine drugs should likely depend on different mechanisms from current 5-HT-related drugs.