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In well-perfused tissues, interstitial composition resembles capillary plasma. Solid tumors break this norm because cancer cell proliferation outpaces vascular expansion, leading to a diffusion-limited tumor microenvironment (TME) that is notably depleted of oxygen and enriched in acids. The magnitude of tumor acidosis; its chemical composition in terms of [CO₂] and [HCO₃⁻] (components of the major extracellular buffer); and its relationship with hypoxia are not intuitive to predict but important to know for designing experiments and contextualising results. We address these timely questions using mathematical models of a monolayer, spheroid, and poorly-perfused tissue. Our simulations suggest a physiologically realistic TME pH range of 6.7–7.4, reveal a prominence of hypercapnia, and indicate varying levels of HCO₃⁻ depletion or accumulation arising from fermentation and respiration, respectively. The trajectories of tumor hypoxia and acidosis depend on the balance between aerobic and anaerobic pathways, with important consequences on hypoxic signaling where many responses are pH-sensitive.

Accurate and timely genome replication is a universal feature of living organisms and a prerequisite for cell proliferation. In eukaryotes, genomic DNA replication initiates in two steps, origin licensing and origin firing, reflecting the loading and activation of the MCM replicative helicase motor on origin DNA. Biochemical reconstitution of these steps in the budding yeast model system signified a major advance towards understanding the molecular and structural details of eukaryotic replication initiation events. With recent successes in reconstituting origin licensing with purified human proteins, a mechanistic picture is beginning to emerge on how DNA replication initiates in higher eukaryotes and how it deviates from the paradigms established in budding yeast. In this review, we highlight similarities and differences in licensing mechanisms between yeast and metazoa.

Recapitulation of the nuclear auxin response pathway in yeast led to the hypothesis that corepressors prime loci for rapid bursts of transcription. Specifically, the TPL corepressor, which inhibits transcription in the absence of auxin, interfaces with Mediator and core components of the transcription pre-initiation complex (PIC). Once auxin is perceived, RNA Pol-II is likely to essentially displace TPL, allowing for rapid transcription initiation (and likely re-firing). Here, we present the current evidence supporting the role of TPL-type corepressors in multiple levels of transcriptional control, including modulation of regulatory transcription factor activity, interactions between cis-elements and the core promoter, and in organizing multiple loci within the nucleoplasm. We also highlight critical areas for future investigations.

The synaptonemal complex (SC), a hallmark of meiosis, is a zipper-like protein assembly that links homologous chromosomes to regulate their recombination and segregation. With its characteristic ladder-like structure bridging paired homologs, the SC possesses unique biochemical and biophysical properties that influence both the number and distribution of crossovers. Although its ultrastructure is strikingly similar across eukaryotes, the molecular mechanisms underlying SC assembly and regulation are remarkably diverse, reflecting both conserved principles and evolutionary innovation. In this review, we synthesize current knowledge of the pathways that promote homologous synapsis across diverse model organisms. We focus on how synapsis initiation is coordinated with other meiotic processes, particularly homolog pairing and recombination, and highlight emerging themes, including the spatial and temporal regulation of SC assembly and the conserved molecular modules that couple SC assembly to recombination sites.

Laplane et al. recently provided a valuable framework for understanding cancer evolution through multilevel selection (MLS), distinguishing between MLS1, where groups differ in persistence based on the traits of their constituent cells but do not reproduce or evolve group-level adaptations, and MLS2, where groups themselves reproduce and possess emergent fitness distinct from that of individual cells. However, as the authors themselves acknowledge, applying MLS2 to metastasis is challenging for several reasons. We argue that, rather than behaving as isolated evolutionary units, tumor sites function as components of a distributed system. This perspective suggests that metastasis may be better understood through the lens of selection for function, a framework that explains how traits contributing to system-level persistence can be maintained without requiring group-level reproduction. This approach complements MLS theory and helps account for the resilience of the metastatic system as a whole, namely, the persistence and coordination of multiple tumor sites functioning as a collective rather than as isolated tumors, beyond classical Darwinian models. It also aligns with the view that metastasis may reflect the reactivation of ancient cellular programs in a novel, nonreproductive context.