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In eukaryotes, cell division requires coordination between the nucleus and cytoplasm. Entry into cell division is driven by cyclin-dependent kinases (CDKs), which need a cyclin binding partner for their activity. In Schizosaccharomyces pombe (fission yeast), the B-type cyclin Cdc13 is essential and sufficient for cell cycle progression and is strongly enriched in the nucleus. Here, we show that a fraction of Cdc13 is exported from the nucleus to the cytoplasm just prior to mitosis. This export could be critical to propagate CDK activity throughout the cell. Mutating three Cdc13 nuclear localization signals (NLSs) led to precocious enrichment of Cdc13 in the cytoplasm but did not accelerate mitotic entry, indicating that the export is not sufficient to trigger entry into mitosis. The export coincides with spindle pole body integration into the nuclear envelope and may be required to coordinate nuclear and cytoplasmic signalling required for this integration. The onset and stop of Cdc13 nuclear export are remarkably abrupt, underscoring that S. pombe mitotic entry consists of several switch-like transitions over the course of minutes. Our findings add another instance to the various cyclin nuclear transport events known to occur at critical cell cycle transitions throughout eukaryotes.

The sustainability of aquaculture is challenged by limited fishmeal and fish oil supplies, key sources of long-chain polyunsaturated fatty acids (LC-PUFA) such as eicosapentaenoic acid (EPA, 20:5 n-3), docosahexaenoic acid (DHA, 22:6 n-3) and arachidonic acid (ARA, 20:4 n-6), essential for fish health and product quality. Polychaetes represent a promising alternative. While marine polychaetes show complete LC-PUFA biosynthetic pathways involving elongases (Elovl), front-end desaturases (Fed), and methyl-end desaturases (ω des), freshwater species remain poorly studied. We hypothesize that freshwater-adapted polychaetes exhibit enhanced LC-PUFA biosynthesis to compensate for limited dietary sources in freshwater environments. This study focuses on Namalycastis rhodochorde, a freshwater nereid polychaete found in Southeast Asia. We isolated and characterized elongase and desaturase genes from N. rhodochorde using a yeast-based heterologous expression system. Our results revealed three Elovl (Elovl2/5, Elovl4, Elovl1/7) that elongate PUFA substrates from C₁₈ to C₂₂, two Fed (Fed1 with Δ5 and Fed2 with dual Δ6/Δ8 activities), and two ω des: a Δ12 desaturase enabling linoleic acid (18:2 n-6) synthesis, and an ω3 desaturase converting n-6 into n-3 PUFA. These findings indicate that N. rhodochorde has the enzymatic capacity to synthesize LC-PUFA like ARA and EPA, supporting its potential for sustainable biomass production using low-nutrient substrates.

Hibernation is a remarkable physiological adaptation in many mammals, characterized by prolonged torpor and profound metabolic suppression. Despite its importance, the molecular mechanisms regulating mitochondrial-derived gene expression during hibernation remain poorly understood. In this study, we analysed mitochondrial gene expression across multiple tissues of the hibernating thirteen-lined ground squirrel (Ictidomys tridecemlineatus) using publicly available RNA sequencing (RNA-seq) data. We assessed all known mitochondrial DNA-derived transcripts-including mitochondrial mRNAs, mitochondrial-derived peptides and proteins (MDPs), rRNAs, and long non-coding RNAs (lncRNAs)-in the liver, adrenal gland, three brain regions, and brown adipose tissue (BAT) across different hibernation states. Our findings reveal distinct tissue-specific expression patterns of mitochondrial transcripts. Differential expression was observed in three of the six tissues analysed (liver, adrenal gland, and BAT) while no significant changes were detected in the three brain regions. In tissues exhibiting differential expression, a consistent pattern emerged: lncRNAs such as Mdl1, Mdl1as, and lncCyb were generally upregulated, whereas mRNAs, including a novel transcript encoding the putative mitochondrial protein Rudel, were predominantly downregulated. These results provide new insights into mitochondrial gene regulation during hibernation and highlight tissue-specific adaptations at the level of mitochondrial gene expression.

IκB kinase alpha (IKKα) is a serine/threonine kinase originally known for its role in nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signalling, which integrates inflammatory processes and cancer. IKKα can function within the IKK complex in canonical NF-κB signalling, alongside its homologous family member, IKKβ, and regulatory subunit IKKγ (NEMO). However, a key role for IKKα is its ability to promote non-canonical NF-κB signalling. Additionally, the dynamic ability of IKKα to shuttle between the cytosol and nucleus, mediates NF-κB-independent effects which further its role in inflammation and tumour progression. More recently, an endosomal-generated, nuclear-active IKKα isoform, p45-IKKα has been discovered and implicated in cancer and chemoresistance. This review focuses on current knowledge of the complex and intricate roles of nuclear and cytosolic IKKα in promoting tumour progression. By highlighting the molecular roles of IKKα in several cancer subtypes, and its integral roles in many of the hallmarks of cancer throughout this review, we highlight the therapeutic potential of IKKα as a future anti-cancer drug target.

Amino acids are essential for normal physiological functions, and disruptions in their circulating concentrations are implicated in the pathophysiology of various diseases. Therefore, understanding the mechanisms that regulate circulating amino acid levels in normal physiology is of critical importance. Evidence indicates that in healthy mammals, post-absorptive circulating levels of essential amino acids are maintained within a range that varies little from day to day or following bidirectional changes in dietary protein intake. This suggests the presence of homeostatic control mechanisms. Here, we propose a conceptual framework for the homeostatic regulation of essential amino acid availability, emphasizing the role of the brain in generating feedback controls to restore baseline levels acutely after a meal and during chronic changes in dietary protein intake. We review current evidence supporting brain amino acid sensing as a component of this regulatory system, integrating peripheral and central signals to modulate dietary protein intake and peripheral amino acid metabolism. We highlight major knowledge gaps regarding the specific neural circuits, molecular mechanisms and physiological outcomes of brain amino acid sensing. Future inquiry using the proposed framework and addressing these gaps will significantly enhance our understanding of the pathways involved in the maintenance of circulating amino acid availability and the regulation of lean mass in health, disease states or in response to therapeutic strategies for metabolic diseases.

Oxytocin (OXT) neurons in the paraventricular nucleus of the hypothalamus (PVN), which send projections to the medial amygdala (MeA) and the bed nucleus of the stria terminalis (BnST), are implicated in regulation of prosocial-emotional behaviours and abnormalities resembling autism spectrum disorders (ASD). Compared with standard C57BL6J (B6) mice, BTBR mice, a behaviour-based ASD model, exhibited decreased densities of OXT^PVN neurons and attenuated OXT neuronal responses to a social encounter. OXT receptor mRNA expressions in the MeA and BnST as a response to a social encounter were blunted in BTBR mice. OXT promoter retrograde viral tracing revealed that the OXT^PVN→BnST projections were defective in those BTBR mice. Thus, chemogenetic excitation of OXT^PVN→MeA neurons using OXT promoter adeno-associated viruses (AAV) enhanced anxiety-like behaviour and facilitated social investigation in both strains, while excitation of OXT^PVN→BnST neurons attenuated anxiety-like behaviour along with social investigation in B6 mice and failed to induce a change in their socio-emotional behaviours in BTBR mice. Altogether, OXT circuits serve as a key regulator for socio-emotional behaviour; MeA-OXT projection facilitates social investigation and anxiety-like behaviour, while BnST-OXT projection conversely attenuates these behaviours; hence a defect of the OXT^PVN→BnST circuits contributes to the development of ASD-like social phenotypes in BTBR mice.

Metamonada is a eukaryotic supergroup of free-living and parasitic anaerobic protists. Their characteristic feature is the presence of highly reduced mitochondria that have lost the ability to produce ATP by oxidative phosphorylation and in some cases even by substrate phosphorylation, with all ATP being imported from the cytosol. Given this striking difference in cellular ATP metabolism when compared to aerobic mitochondria, we studied the presence of mitochondrial carrier proteins (MCPs) mediating the transport of ATP across the inner mitochondrial membrane. Our bioinformatic analyses revealed remarkable reduction of MCP repertoire in Metamonada with striking loss of the major ADP/ATP carrier (AAC). Instead, nearly all species retained carriers orthologous to human SLC25A43 protein, a little-characterized MCP. Heterologous expression of metamonad SLC25A43 carriers confirmed their mitochondrial localization, and functional analysis revealed that SLC25A43 orthologues represent a distinct group of ATP transporters, which we designate as ATP-importing carriers (AIC). Together, our findings suggest that AIC facilitate the ATP import into highly reduced anaerobic mitochondria, compensating for their diminished or absent energy metabolism.

Diplonemids are highly diverse and abundant marine plankton with significant ecological importance. However, little is known about their biology, even in the model diplonemid Paradiplonema papillatum whose genome sequence is available. Examining the subcellular localization of proteins using fluorescence microscopy is a powerful approach to infer their putative function. Here, we report a plasmid-based method that enables YFP-tagging of a gene at the endogenous locus. By examining the localization of proteins whose homologs are involved in chromosome organization or segregation in other eukaryotes, we discovered several notable features in mitotically dividing P. papillatum cells. Cohesin is enriched on condensed interphase chromatin. During mitosis, chromosomes organize into two rings (termed mitotic rings herein) that surround the elongating nucleolus and align on a bipolar spindle. Homologs of chromosomal passenger complex components (INCENP, two Aurora kinases and KIN-A), a CLK1 kinase, meiotic chromosome axis protein SYCP2L1, spindle checkpoint protein Mad1 and microtubule regulator XMAP215 localize in between the two mitotic rings. In contrast, a Mad2 homolog localizes near basal bodies as in trypanosomes. By representing the first molecular characterization of mitotic mechanisms in P. papillatum and raising many questions, this study forms the foundation for dissecting mitotic mechanisms in diplonemids.

Diapause is a fascinating form of biological dormancy that is employed by a broad array of animals as a survival strategy to endure adverse environmental conditions. This unique dormant state can suspend organismal development until a more favourable condition arises, giving the species the greatest chance to survive as a whole. Remarkably, while following the same principle of suspending development, diapause exists in different forms and can occur at various stages before reaching the adult form. Functionally, with multiple evolutionary origins across the animal kingdom, diapause demonstrates the ability to respond to diverse environmental challenges while converging to maintain the same core function of suspending development. At the physiological level, these different diapause states share a similar metabolic adaptation to conserve resources and energy throughout dormancy. Underneath, the same genes have been repeatedly identified as regulators and effectors of diapause at different developmental stages in both invertebrates and vertebrates. This suggests the presence of a conserved molecular programme comprised of the same set of key genes repeatedly reprogrammed and utilized at the core of diapause. The knowledge of diapause from the organismal to molecular levels, together, should serve as a useful window to better understand the biology of dormancy.

Several biological processes, including transcriptional regulation by transcription factors (TFs), are dose-dependent. At the mathematical level, dose-dependent processes can be modelled by fitting dose-response curves, for istance, employing Hill-type equations. At the experimental level, however, quantitatively regulating, or tuning, endogenous gene expression to characterize dose-dependent processes is challenging. Here, existing methods to fine-tune endogenous gene expression are compared and contrasted. Relatively small TF dosage variations have been shown to underpin cell fate decisions. Nonetheless, the current understanding of the molecular mechanisms by which TFs quantitatively regulate gene expression is limited, due to the paucity of genome-wide studies in endogenous and physiological conditions. Recent works combining quantitative perturbations of TFs and genome-wide response analyses are untangling an underexplored layer of transcriptional control. At the same time, new questions are emerging in the field, which will require further technological advancements in order to be addressed.