Center for Interdisciplinary Research in Biology

Abstract Linkage Disequilibrium (LD) is a measure of the statistical association, within a population, between alleles present at different loci. We first briefly explain how LD, and in particular its decay as a function of the genetic distance between the two loci, is expected to be affected by mutation, recombination, selection, drift and demography. We then focus on three specific, widely used measures of LD:D, |D′|, andr2, in three different contexts: absence of recombination, a single recombination event, and an infinite amount of recombination events. We produce detailed characterizations of these three statistics under different demographic scenarios, with simulations, and with analytic results forD. We classify recombination events into four types and rank them according to their respective frequencies and effects. Finally, we provide recommendations for the uses of the different statistics and suggest applications of LD measures in the absence of recombination.

Conformational changes are observed in many enzymes, but their role in catalysis is highly controversial. Here we present a theoretical model that illustrates how rigid catalysts can be fundamentally limited and how a conformational change induced by substrate binding can overcome this limitation, ultimately enabling barrier-free catalysis. The model is deliberately minimal, but the principle it illustrates is general and consistent with unique features of proteins as well as with previous informal proposals to explain the superiority of enzymes over other classes of catalysts. Implementing the discriminative switch suggested by the model could help overcome limitations currently encountered in the design of artificial catalysts.

Connexin 43, an astroglial gap junction protein, is enriched in perisynaptic astroglial processes and plays major roles in synaptic transmission. We have previously found that astroglial Cx43 controls synaptic glutamate levels and allows for activity-dependent glutamine release to sustain physiological synaptic transmissions and cognitiogns. However, whether Cx43 is important for the release of synaptic vesicles, which is a critical component of synaptic efficacy, remains unanswered. Here, using transgenic mice with a glial conditional knockout of Cx43 (Cx43−/−), we investigate whether and how astrocytes regulate the release of synaptic vesicles from hippocampal synapses. We report that CA1 pyramidal neurons and their synapses develop normally in the absence of astroglial Cx43. However, a significant impairment in synaptic vesicle distribution and release dynamics were observed. In particular, the FM1-43 assays performed using two-photon live imaging and combined with multi-electrode array stimulation in acute hippocampal slices, revealed a slower rate of synaptic vesicle release in Cx43−/− mice. Furthermore, paired-pulse recordings showed that synaptic vesicle release probability was also reduced and is dependent on glutamine supply via Cx43 hemichannel (HC). Taken together, we have uncovered a role for Cx43 in regulating presynaptic functions by controlling the rate and probability of synaptic vesicle release. Our findings further highlight the significance of astroglial Cx43 in synaptic transmission and efficacy.

Oxygen deprivation induces multiple changes at the cellular and organismal levels, and its re-supply also brings another special physiological status. We have investigated the effects of hypoxia/re-oxygenation on embryonic growth using the zebrafish model: hypoxia slows embryonic growth, but re-oxygenation induces growth spurt or catch-up growth. The mitogen-activated kinase (MAPK)-pathway downstream insulin-like growth factor (IGF/Igf) has been revealed to positively regulate the re-oxygenation-induced catch-up growth, and the role of reactive oxygen species generated by environmental oxygen fluctuation is potentially involved in the phenomenon. Here, we report the role of NADPH-oxidase (Nox)-dependent hydrogen peroxide (H2O2) production in the MAPK-activation and catch-up growth. The inhibition of Nox significantly blunted catch-up growth and MAPK-activity. Amongst two zebrafish insulin receptor substrate 2 genes (irs2a and irs2b), the loss of irs2b, but not its paralog irs2a, resulted in blunted MAPK-activation and catch-up growth. Furthermore, irs2b forcedly expressed in mammalian cells allowed IGF-MAPK augmentation in the presence of H2O2, and the irs2b deficiency completely abolished the somatotropic action of Nox in re-oxygenation condition. These results indicate that redox signaling alters IGF/Igf signaling to facilitate hypoxia/re-oxygenation-induced embryonic growth compensation.

Evaluating the characteristics of emerging SARS-CoV-2 variants of concern is essential to inform pandemic risk assessment. A variant may grow faster if it produces a larger number of secondary infections (“R advantage”) or if the timing of secondary infections (generation time) is better. So far, assessments have largely focused on deriving the R advantage assuming the generation time was unchanged. Yet, knowledge of both is needed to anticipate the impact. Here, we develop an analytical framework to investigate the contribution of both the R advantage and generation time to the growth advantage of a variant. It is known that selection on a variant with larger R increases with levels of transmission in the community. We additionally show that variants conferring earlier transmission are more strongly favored when the historical strains have fast epidemic growth, while variants conferring later transmission are more strongly favored when historical strains have slow or negative growth. We develop these conceptual insights into a new statistical framework to infer both the R advantage and generation time of a variant. On simulated data, our framework correctly estimates both parameters when it covers time periods characterized by different epidemiological contexts. Applied to data for the Alpha and Delta variants in England and in Europe, we find that Alpha confers a+54% [95% CI, 45–63%] R advantage compared to previous strains, and Delta +140% [98–182%] compared to Alpha, and mean generation times are similar to historical strains for both variants. This work helps interpret variant frequency dynamics and will strengthen risk assessment for future variants of concern.

Kingman’s (1978) representation theorem (J. Lond. Math. Soc. (2) 18 (1978) 374–380) states that any exchangeable partition of ℕ can be represented as a paintbox based on a random mass-partition. Similarly, any exchangeable composition (i.e., ordered partition of ℕ) can be represented as a paintbox based on an interval-partition (Gnedin (1997) Ann. Probab. 25 (1997) 1437–1450). Our first main result is that any exchangeable coalescent process (not necessarily Markovian) can be represented as a paintbox based on a random nondecreasing process valued in interval-partitions, called nested interval-partition, generalizing the notion of comb metric space introduced in Lambert and Uribe Bravo (2017) (p-Adic Numbers Ultrametric Anal. Appl. 9 (2017) 22–38) to represent compact ultrametric spaces. As a special case, we show that any Λ-coalescent can be obtained from a paintbox based on a unique random nested interval partition called Λ-comb, which is Markovian with explicit transitions. This nested interval-partition directly relates to the flow of bridges of Bertoin and Le Gall (2003) (Probab. Theory Related Fields 126 (2003) 261–288). We also display a particularly simple description of the so-called evolving coalescent (Pfaffelhuber and Wakolbinger (2006) Stochastic Process. Appl. 116 (2006) 1836–1859) by a comb-valued Markov process. Next, we prove that any ultrametric measure space U, under mild measure-theoretic assumptions on U, is the leaf set of a tree composed of a separable subtree called the backbone, on which are grafted additional subtrees, which act as star-trees from the standpoint of sampling. Displaying this so-called weak isometry requires us to extend the Gromov-weak topology of Greven, Pfaffelhuber and Winter (2009) (Probab. Theory Related Fields 145 (2009) 285–322), that was initially designed for separable metric spaces, to nonseparable ultrametric spaces. It allows us to show that for any such ultrametric space U, there is a nested interval-partition which is (1) indistinguishable from U in the Gromov-weak topology; (2) weakly isometric to U if U has a complete backbone; (3) isometric to U if U is complete and separable.

The emergence of SARS-CoV-2 variant 20I/501Y.V1 (VOC-202012/1 or GR/501Y.V1) is concerning given its increased transmissibility. We reanalysed 11,916 PCR-positive tests (41% of all positive tests) performed on 7–8 January 2021 in France. The prevalence of 20I/501Y.V1 was 3.3% among positive tests nationwide and 6.9% in the Paris region. Analysing the recent rise in the prevalence of 20I/501Y.V1, we estimate that, in the French context, 20I/501Y.V1 is 52–69% more transmissible than the previously circulating lineages, depending on modelling assumptions.

Reactive astrocytes are astrocytes undergoing morphological, molecular, and functional remodeling in response to injury, disease, or infection of the CNS. Although this remodeling was first described over a century ago, uncertainties and controversies remain regarding the contribution of reactive astrocytes to CNS diseases, repair, and aging. It is also unclear whether fixed categories of reactive astrocytes exist and, if so, how to identify them. We point out the shortcomings of binary divisions of reactive astrocytes into good-vs-bad, neurotoxic-vs-neuroprotective or A1-vs-A2. We advocate, instead, that research on reactive astrocytes include assessment of multiple molecular and functional parameters-preferably in vivo-plus multivariate statistics and determination of impact on pathological hallmarks in relevant models. These guidelines may spur the discovery of astrocyte-based biomarkers as well as astrocyte-targeting therapies that abrogate detrimental actions of reactive astrocytes, potentiate their neuro- and glioprotective actions, and restore or augment their homeostatic, modulatory, and defensive functions.

Abstract Retinal ganglion cell axons provide the only link between the light sensitive and photon transducing neural retina and visual centers of the brain. Retinal ganglion cell axon degeneration occurs in a number of blinding diseases and the ability to stimulate axon regeneration from surviving ganglion cells could provide the anatomic substrate for restoration of vision. OTX2 is a homeoprotein transcription factor expressed in the retina and previous studies showed that, in response to stress, exogenous OTX2 increases thein vitroandin vivosurvival of retinal ganglion cells. The present results show that, in addition to promoting adult retinal ganglion cell survival, OTX2 also stimulates the regeneration of their axonsin vitroandin vivo. This dual activity of OTX2 on retinal ganglion cell survival and regeneration is of potential interest for degenerative diseases affecting this cell type.