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Self-organized pattern formation in the developing mouse neural tube by a temporal relay of BMP signaling
No full textDeveloping tissues interpret dynamic changes in morphogen activity to generate cell type diversity. To quantitatively study bone morphogenetic protein (BMP) signaling dynamics in the mouse neural tube, we developed an embryonic stem cell differentiation system tailored for growing tissues. Differentiating cells form striking self-organized patterns of dorsal neural tube cell types driven by sequential phases of BMP signaling that are observed both in vitro and in vivo. Data-driven biophysical modeling showed that these dynamics result from coupling fast negative feedback with slow positive regulation of signaling by the specification of an endogenous BMP source. Thus, in contrast to relays that propagate morphogen signaling in space, we identify a BMP signaling relay that operates in time. This mechanism allows for a rapid initial concentration-sensitive response that is robustly terminated, thereby regulating balanced sequential cell type generation. Our study provides an experimental and theoretical framework to understand how signaling dynamics are exploited in developing tissues
Biallelic NDUFA13 variants lead to a neurodevelopmental phenotype with gradual neurological impairment
No full textBiallelic variants in NADH (nicotinamide adenine dinucleotide (NAD) + hydrogen (H))-ubiquinone oxidoreductase 1 alpha subcomplex 13 have been linked to mitochondrial complex I deficiency, nuclear type 28, based on three affected individuals from two families. With only two families reported, the clinical and molecular spectrum of NADH-ubiquinone oxidoreductase 1 alpha subcomplex 13–related diseases remains unclear. We report 10 additional affected individuals from nine independent families, identifying four missense variants (including recurrent c.170G > A) and three ultra-rare or novel predicted loss-of-function biallelic variants. Updated clinical–radiological data from previously reported families and a literature review compiling clinical features of all reported patients with isolated complex I deficiency caused by 43 genes encoding complex I subunits and assembly factors are also provided. Our cohort (mean age 7.8 ± 5.4 years; range 2.5–18) predominantly presented a moderate-to-severe neurodevelopmental syndrome with oculomotor abnormalities (84%), spasticity/hypertonia (83%), hypotonia (69%), cerebellar ataxia (66%), movement disorders (58%) and epilepsy (46%). Neuroimaging revealed bilateral symmetric T2 hyperintense substantia nigra lesions (91.6%) and optic nerve atrophy (66.6%). Protein modeling suggests missense variants destabilize a critical junction between the hydrophilic and membrane arms of complex I. Fibroblasts from two patients showed reduced complex I activity and compensatory complex IV activity increase. This study characterizes NADH-ubiquinone oxidoreductase 1 alpha subcomplex 13–related disease in 13 individuals, highlighting genotype–phenotype correlations
On the (k + 2, k)-problem of Brown, Erdős, and Sós for k = 5,6,7
No full textLet f(r)(n;s,k) denote the maximum number of edges in an n-vertex r-uniform hypergraph containing no subgraph with k edges and at most s vertices. Brown, Erdős and Sós [New directions in the theory of graphs (Proc. Third Ann Arbor Conf., Univ. Michigan 1971), pp. 53--63, Academic Press 1973] conjectured that the limit limn→∞n−2f(3)(n;k+2,k) exists for all k. The value of the limit was previously determined for k=2 in the original paper of Brown, Erdős and Sós, for k=3 by Glock [Bull. Lond. Math. Soc. 51 (2019) 230--236] and for k=4 by Glock, Joos, Kim, Kühn, Lichev and Pikhurko [arXiv:2209.14177, accepted by Proc. Amer. Math. Soc.] while Delcourt and Postle [arXiv:2210.01105, accepted by Proc. Amer. Math. Soc.] proved the conjecture (without determining the limiting value).
In this paper, we determine the value of the limit in the Brown-Erdős-Sós Problem for k∈{5,6,7}. More generally, we obtain the value of limn→∞n−2f(r)(n;rk−2k+2,k) for all r≥3 and k∈{5,6,7}. In addition, by combining these new values with recent results of Bennett, Cushman and Dudek [arXiv:2309.00182] we obtain new asymptotic values for several generalised Ramsey numbers
A coarse-grained model for aqueous two-phase systems: Application to ferrofluids
No full textAqueous two-phase systems (ATPSs), phase-separating solutions of water soluble but mutually immiscible molecular species, offer fascinating prospects for selective partitioning, purification, and extraction. Here, we formulate a general Brownian dynamics based coarse-grained simulation model for an ATPS of two water soluble but mutually immiscible polymer species. Including additional solute species into the model is straightforward, which enables capturing the assembly and partitioning response of, e.g., nanoparticles (NPs), additional macromolecular species, or impurities in the ATPS. We demonstrate that the simulation model captures satisfactorily the phase separation, partitioning, and interfacial properties of an actual ATPS using a model ATPS in which a polymer mixture of dextran and polyethylene glycol (PEG) phase separates, and magnetic NPs selectively partition into one of the two polymeric phases. Phase separation and NP partitioning are characterized both via the computational model and experimentally, under different conditions. The simulation model captures the trends observed in the experimental system and quantitatively links the partitioning behavior to the component species interactions. Finally, the simulation model reveals that the ATPS interface fluctuations in systems with magnetic NPs as a partitioned species can be controlled by the magnetic field at length scales much smaller than those probed experimentally to date
Unilateral incentive alignment in two-agent stochastic games
No full textMultiagent learning is challenging when agents face mixed-motivation interactions, where conflicts of interest arise as agents independently try to optimize their respective outcomes. Recent advancements in evolutionary game theory have identified a class of “zero-determinant” strategies, which confer an agent with significant unilateral control over outcomes in repeated games. Building on these insights, we present a comprehensive generalization of zero-determinant strategies to stochastic games, encompassing dynamic environments. We propose an algorithm that allows an agent to discover strategies enforcing predetermined linear (or approximately linear) payoff relationships. Of particular interest is the relationship in which both payoffs are equal, which serves as a proxy for fairness in symmetric games. We demonstrate that an agent can discover strategies enforcing such relationships through experience alone, without coordinating with an opponent. In finding and using such a strategy, an agent (“enforcer”) can incentivize optimal and equitable outcomes, circumventing potential exploitation. In particular, from the opponent’s viewpoint, the enforcer transforms a mixed-motivation problem into a cooperative problem, paving the way for more collaboration and fairness in multiagent systems
Arabidopsis phospholipase Dζ2 facilitates vacuolar acidification and autophagy under phosphorus starvation by interacting with VATD
No full textVacuolar acidification is crucial for the homeostasis of intracellular pH and the recycling of proteins and nutrients in cells, thereby playing important roles in various physiological processes related to vacuolar function. The key factors regulating vacuolar acidification and underlying mechanisms remain unclear. Here, we report that Arabidopsis phospholipase Dζ2 (PLDζ2) promotes the acidification of the vacuolar lumen to stimulate autophagic degradation under phosphorus deficiency. The pldζ2 mutant massively accumulates autophagic structures while exhibiting premature leaf senescence under nutrient starvation. Impaired autophagic flux, lytic vacuole morphology, and lytic degradation in pldζ2 indicate that PLDζ2 regulates autophagy by affecting the vacuolar function. PLDζ2 locates in both tonoplast and cytoplasm. Genetic, structural, and biochemical studies demonstrate that PLDζ2 directly interacts with vacuolar-type ATPase (V-ATPase) subunit D (VATD) to promote vacuolar acidification and autophagy under phosphorus starvation. These findings reveal the importance of V-ATPase and vacuolar pH in autophagic activity and provide clues in elucidating the regulatory mechanism of vacuolar acidification
Can supermassive stars form in protogalaxies due to internal Lyman-Werner feedback?
No full textPopulation III stars are possible precursors to early supermassive black holes (BHs). The presence of soft UV Lyman–Werner (LW) background radiation can suppress Population III star formation in minihaloes and allow them to form in pristine atomic-cooling haloes. In the absence of molecular hydrogen (H2) cooling, atomic-cooling haloes enable rapid collapse with suppressed fragmentation. High background LW fluxes from preceding star-formation have been proposed to dissociate H2. This flux can be supplemented by LW radiation from one or more Population III star(s) in the same halo, reducing the necessary background level. Here, we consider atomic-cooling haloes in which multiple protostellar cores form close to one another nearly simultaneously. We assess whether the first star’s LW radiation can dissociate nearby
, enabling rapid accretion on to a nearby protostellar core, and the prompt formation of a second, supermassive star (SMS) from warm, atomically-cooled gas. We use a set of hydrodynamical simulations with the code enzo, with identical LW backgrounds centred on a halo with two adjacent collapsing gas clumps. When an additional large local LW flux is introduced, we observe immediate reductions in both the accretion rates and the stellar masses that form within these clumps. While the LW flux reduces the H2 fraction and increases the gas temperature, the halo core’s potential well is too shallow to promptly heat the gas to >1000 K and increase the second protostar’s accretion rate. We conclude that this internal LW feedback scenario is unlikely to facilitate SMS or massive BH seed formation
Tuning conductance in BODIPY-based single-molecule junctions
No full textHere, we present a foundational investigation of charge transport through three BODIPY-based molecules using the scanning tunneling microscope–break junction (STM-BJ) technique. We demonstrate that molecular conductance through the BODIPY core can be measured by introducing aurophilic linkers at the 2,6-positions. By varying these linkers, we systematically modulate the frontier molecular orbital energies and fine-tune transport behavior. Our experimental results are supported by DFT-based calculations, which feature a new computationally efficient correction to standard PBE-level transmission predictions. Together, these findings establish the viability of BODIPY-based systems for molecular junction applications and lay the groundwork for future studies of their single-molecule optoelectronic properties
Joint estimation of paternity, sibships and pollen dispersal in a snapdragon hybrid zone
No full textInferring genealogical relationships of wild populations is useful because it gives direct estimates of mating patterns and variance in reproductive success. Inference can be improved by including information about parentage shared between siblings, or by modelling phenotypes or population data related to mating. However, we currently lack a framework to infer parent–offspring relationships, sibships and population parameters in a single analysis. To address this, we here extend a previous method, Fractional Analysis of Paternity and Sibships, to include population data for the case where one parent is known. We illustrate this with the example of pollen dispersal in a natural hybrid zone population of the snapdragon Antirrhinum majus. Pollen dispersal is leptokurtic, with half of mating events occurring within 30 m, but with a long tail of mating events up to 859 m. Using simulations, we find that both sibship and population information substantially improve pedigree reconstruction, and that we can expect to resolve median dispersal distances with high accuracy
LIPIcs
No full textWe generalize a classical result by Boris Delaunay that introduced Delaunay triangulations. In particular, we prove that for a locally finite and coarsely dense generic point set A in ℝ^d, every generic point of ℝ^d belongs to exactly binom(d+k,d) simplices whose vertices belong to A and whose circumspheres enclose exactly k points of A. We extend this result to the cases in which the points are weighted, and when A contains only finitely many points in ℝ^d or in ^d. Furthermore, we use the result to give a new geometric proof for the fact that volumes of hypersimplices are Eulerian numbers