Malaria is caused by the rapid proliferation of Plasmodium parasites in patients and disease severity correlates with the number of infected red blood cells in circulation. Parasite multiplication within red blood cells is called schizogony and occurs through an atypical multinucleated cell division mode. The mechanisms regulating the number of daughter cells produced by a single progenitor are poorly understood. We investigated underlying regulatory principles by quantifying nuclear multiplication dynamics in Plasmodium falciparum and knowlesi using super-resolution time-lapse microscopy. This confirmed that the number of daughter cells was consistent with a model in which a counter mechanism regulates multiplication yet incompatible with a timer mechanism. P. falciparum cell volume at the start of nuclear division correlated with the final number of daughter cells. As schizogony progressed, the nucleocytoplasmic volume ratio, which has been found to be constant in all eukaryotes characterized so far, increased significantly, possibly to accommodate the exponentially multiplying nuclei. Depleting nutrients by dilution of culture medium caused parasites to produce fewer merozoites and reduced proliferation but did not affect cell volume or total nuclear volume at the end of schizogony. Our findings suggest that the counter mechanism implicated in malaria parasite proliferation integrates extracellular resource status to modify progeny number during blood stage infection.

Malaria-causing parasites proliferate within erythrocytes through schizogony, forming multinucleated stages before cellularization. Nuclear multiplication does not follow a strict geometric 2 n progression, and each proliferative cycle produces a variable number of progeny. Here, by tracking nuclei and DNA replication, we show that individual nuclei replicate their DNA at different times, despite residing in a shared cytoplasm. Extrapolating from experimental data using mathematical modeling, we provide strong indication that a limiting factor exists, which slows down the nuclear multiplication rate. Consistent with this prediction, our data show that temporally overlapping DNA replication events were significantly slower than partially overlapping or nonoverlapping events. Our findings suggest the existence of evolutionary pressure that selects for asynchronous DNA replication, balancing available resources with rapid pathogen proliferation.

In multicellular organisms, antiviral defense mechanisms evoke a reliable collective immune response despite the noisy nature of biochemical communication between tissue cells. A molecular hub of this response, the interferon I receptor (IFNAR), discriminates between ligand types by their affinity regardless of concentra-tion. To understand how ligand type can be decoded robustly by a single receptor, we frame ligand discrimination as an information-theoretic problem and systematically compare the major classes of receptor architectures: allosteric, homodimerizing, and het-erodimerizing. We demonstrate that asymmetric heterodimers achieve the best discrimination power over the entire physio-logical range of local ligand concentrations. This design enables sensing of ligand presence and type, and it buffers against mod-erate concentration fluctuations. In addition, receptor turnover, which drives the receptor system out of thermodynamic equi-librium, allows alignment of activation points for ligands of different affinities and thereby makes ligand discrimination prac-tically independent of concentration. IFNAR exhibits this optimal architecture, and our findings thus suggest that this special-ized receptor can robustly decode digital messages carried by its different ligands.

We determine the quantum Cramer-Rao bound for the precision with which the oscillator frequency and damping constant of a damped quantum harmonic oscillator in an arbitrary Gaussian state can be estimated. This goes beyond standard quantum parameter estimation of a single mode Gaussian state for which typically a mode of fixed frequency is assumed. We present a scheme through which the frequency estimation can nevertheless be based on the known results for single-mode quantum parameter estimation with Gaussian states. Based on these results, we investigate the optimal measurement time. For measuring the oscillator frequency, our results unify previously known partial results and constitute an explicit solution for a general single-mode Gaussian state. Furthermore, we show that with existing carbon nanotube resonators (see J. Chaste et al.~Nature Nanotechnology 7, 301 (2012)) it should be possible to achieve a mass sensitivity of the order of an electron mass $\text{Hz}^{-1/2}$.

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