VaiPhy: a Variational Inference Based Algorithm for Phylogeny

Phylogenetics is a classical methodology in computational biology that today has become highly relevant for medical investigation of single-cell data, e.g., in the context of cancer development. The exponential size of the tree space is, unfortunately, a substantial obstacle for Bayesian phylogenetic inference using Markov chain Monte Carlo based methods since these rely on local operations. And although more recent variational inference (VI) based methods offer speed improvements, they rely on expensive auto-differentiation operations for learning the variational parameters. We propose VaiPhy, a remarkably fast VI based algorithm for approximate posterior inference in an augmented tree space. VaiPhy produces marginal log-likelihood estimates on par with the state-of-the-art methods on real data and is considerably faster since it does not require auto-differentiation. Instead, VaiPhy combines coordinate ascent update equations with two novel sampling schemes: (i) SLANTIS, a proposal distribution for tree topologies in the augmented tree space, and (ii) the JC sampler, to the best of our knowledge, the first-ever scheme for sampling branch lengths directly from the popular Jukes-Cantor model. We compare VaiPhy in terms of density estimation and runtime. Additionally, we evaluate the reproducibility of the baselines. We provide our code on GitHub: \url{https://github.com/Lagergren-Lab/VaiPhy}.Comment: NeurIPS-22 conference pape

The allometry of proboscis length in Melittidae (Hymenoptera: Apoidae) and an estimate of their foraging distance using museum collections

An appreciation of body size allometry is central for understanding insect pollination ecology. A recent model utilises allometric coefficients for five of the seven extant bee families (Apoidea: Anthophila) to include crucial but difficult-to-measure traits, such as proboscis length, in ecological and evolutionary studies. Melittidae were not included although they are important pollinators in South Africa where they comprise an especially rich and morphologically diverse fauna. We measured intertegular distance (correlated with body size) and proboscis length of 179 specimens of 11 species from three genera of Melittidae. With the inclusion of Melittidae, we tested the between family differences in the allometric scaling coefficients. AIC model selection was used to establish which factors provide the best estimate of proboscis length. We explored a hypothesis that has been proposed in the literature, but which has not been tested, whereby body and range sizes of bees are correlated with rainfall regions. We tested this by using body size measurements of 2109 museum specimens from 56 species of Melittidae and applied the model coefficients to estimate proboscis length and foraging distance. Our results show that with the addition of Melittidae, we retained the overall pattern of significant differences in the scaling coefficient among Apoidea, with our model explaining 98% of the variance in species-level means for proboscis length. When testing the relationship between body size and rainfall region we found no relationship for South African Melittidae. Overall, this study has added allometric scaling coefficients for an important bee family and shown the applicability of using these coefficients when linked with museum specimens to test ecological hypothesi

Multiple Importance Sampling ELBO and Deep Ensembles of Variational Approximations

In variational inference (VI), the marginal log-likelihood is estimated using the standard evidence lower bound (ELBO), or improved versions as the importance weighted ELBO (IWELBO). We propose the multiple importance sampling ELBO (MISELBO), a \textit{versatile} yet \textit{simple} framework. MISELBO is applicable in both amortized and classical VI, and it uses ensembles, e.g., deep ensembles, of independently inferred variational approximations. As far as we are aware, the concept of deep ensembles in amortized VI has not previously been established. We prove that MISELBO provides a tighter bound than the average of standard ELBOs, and demonstrate empirically that it gives tighter bounds than the average of IWELBOs. MISELBO is evaluated in density-estimation experiments that include MNIST and several real-data phylogenetic tree inference problems. First, on the MNIST dataset, MISELBO boosts the density-estimation performances of a state-of-the-art model, nouveau VAE. Second, in the phylogenetic tree inference setting, our framework enhances a state-of-the-art VI algorithm that uses normalizing flows. On top of the technical benefits of MISELBO, it allows to unveil connections between VI and recent advances in the importance sampling literature, paving the way for further methodological advances. We provide our code at \url{https://github.com/Lagergren-Lab/MISELBO}.Comment: AISTATS 202

VaiPhy: a Variational Inference Based Algorithm for Phylogeny

Phylogenetics is a classical methodology in com- putational biology that today has become highly relevant for medical investigation of single-cell data, e.g., in the context of development of can- cer. The exponential size of the tree space is unfortunately a formidable obstacle for current Bayesian phylogenetic inference using Markov chain Monte Carlo based methods since these rely on local operations. And although more re- cent variational inference (VI) based methods of- fer speed improvements, they rely on expensive auto-differentiation operations for learning the variational parameters. We propose VaiPhy, a remarkably fast VI based algorithm for approx- imate posterior inference in an augmented tree space. VaiPhy produces marginal log-likelihood estimates on par with the state-of-the-art meth- ods on real data, and is considerably faster since it does not require auto-differentiation. Instead, VaiPhy combines coordinate ascent update equa- tions with two novel sampling schemes: (i) SLANTIS, a proposal distribution for tree topolo- gies in the augmented tree space, and (ii) the JC sampler, the, to the best of our knowledge, first ever scheme for sampling branch lengths directly from the popular Jukes-Cantor model. We compare VaiPhy in terms of density esti- mation and runtime. Additionally, we evaluate the reproducibility of the baselines. We provide our code on GitHub: https://github.com/ Lagergren-Lab/VaiPhy. QC 20220421</p

VaiPhy: a Variational Inference Based Algorithm for Phylogeny

Phylogenetics is a classical methodology in com- putational biology that today has become highly relevant for medical investigation of single-cell data, e.g., in the context of development of can- cer. The exponential size of the tree space is unfortunately a formidable obstacle for current Bayesian phylogenetic inference using Markov chain Monte Carlo based methods since these rely on local operations. And although more re- cent variational inference (VI) based methods of- fer speed improvements, they rely on expensive auto-differentiation operations for learning the variational parameters. We propose VaiPhy, a remarkably fast VI based algorithm for approx- imate posterior inference in an augmented tree space. VaiPhy produces marginal log-likelihood estimates on par with the state-of-the-art meth- ods on real data, and is considerably faster since it does not require auto-differentiation. Instead, VaiPhy combines coordinate ascent update equa- tions with two novel sampling schemes: (i) SLANTIS, a proposal distribution for tree topolo- gies in the augmented tree space, and (ii) the JC sampler, the, to the best of our knowledge, first ever scheme for sampling branch lengths directly from the popular Jukes-Cantor model. We compare VaiPhy in terms of density esti- mation and runtime. Additionally, we evaluate the reproducibility of the baselines. We provide our code on GitHub: https://github.com/ Lagergren-Lab/VaiPhy. QC 20220421</p

Nectar Uptake of a Long-Proboscid Prosoeca Fly (Nemestrinidae)—Proboscis Morphology and Flower Shape

Several Prosoeca (Nemestinidae) species use a greatly elongated proboscis to drink nectar from long-tubed flowers. We studied morphological adaptations for nectar uptake of Prosoecamarinusi that were endemic to the Northern Cape of South Africa. Our study site was a small isolated area of semi-natural habitat, where the long-tubed flowers of Babiana vanzijliae (Iridaceae) were the only nectar source of P. marinusi, and these flies were the only insects with matching proboscis. On average, the proboscis measured 32.63 ± 2.93 mm in length and less than 0.5 mm in diameter. The short labella at the tip are equipped with pseudotracheae that open at the apical margin, indicating that nectar is extracted out of the floral tube with closed labella. To quantify the available nectar resources, measurements of the nectar volume were taken before the flies were active and after observed flower visits. On average, an individual fly took up approximately 1 µL of nectar per flower visit. The measured nectar quantities and the flower geometry allowed estimations of the nectar heights and predictions of necessary proboscis lengths to access nectar in a range of flower tube lengths

Spleen contraction and Hb elevation after dietary nitrate intake

Ingestion of dietary nitrate ([Formula: see text]) is associated with improved exercise tolerance and reduced oxygen (O2) cost of exercise, ascribed to enhanced mitochondrial efficiency, muscle contractile function, or other factors. Nitrate ingestion has also been found to attenuate the reduction in arterial oxygen saturation ([Formula: see text]) during apnea and to prolong apneic duration. The spleen serves as a dynamic blood pool expelling erythrocytes into the circulation during apnea, and [Formula: see text] and nitric oxide donors may induce vasoactive effects in the mesenteric and splanchnic circulation. Our aim was to investigate the effect of ingestion of concentrated organic [Formula: see text]-rich beetroot juice (BR) on spleen volume and spleen contraction during apnea, and the resulting hemoglobin (Hb) concentration. Eight volunteers performed two apneas of submaximal and maximal duration during prone rest ∼2.5 h after ingesting 70 mL of BR (∼5 mmol [Formula: see text]) or placebo (PL; ∼0.003 mmol [Formula: see text]), on separate days in weighted order. Heart rate and [Formula: see text] were monitored continuously and spleen diameters were measured every minute for triaxial volume calculation. Capillary Hb samples were collected at baseline and after the maximal apnea. Baseline spleen volume was reduced by 66 mL after BR ingestion (22.9%; P = 0.026) and Hb was elevated (+3.0%; P = 0.015). During apneas, spleen contraction and Hb increase were similar between BR and PL conditions (NS). The study shows that dietary [Formula: see text]reduces spleen volume at rest, resulting in increased Hb. This spleen-induced Hb elevation following [Formula: see text] ingestions represents a novel mechanism that could enhance performance in conditions involving exercise, apnea, and hypoxia.NEW &amp; NOTEWORTHY This is the first study to examine changes of spleen volume and circulating Hb following dietary [Formula: see text] supplementation. After dietary [Formula: see text] ingestion, the spleen volume at rest was reduced and Hb was elevated. The spleen contains a dynamic red blood cell reservoir, which can be mobilized and facilitate oxygen transport during various types of physiological stress. This study has revealed an additional, previously unexplored mechanism possibly contributing to the ergogenic effects of dietary [Formula: see text]

A mammalian blood odor component serves as an approach-avoidance cue across phylum border - From flies to humans

Chemosignals are used by predators to localize prey and by prey to avoid predators. These cues vary between species, but the odor of blood seems to be an exception and suggests the presence of an evolutionarily conserved chemosensory cue within the blood odor mixture. A blood odor component, E2D, has been shown to trigger approach responses identical to those triggered by the full blood odor in mammalian carnivores and as such, is a key candidate as a food/alarm cue in blood. Using a multidisciplinary approach, we demonstrate that E2D holds the dual function of affecting both approach and avoidance behavior in a predator-prey predicted manner. E2D evokes approach responses in two taxonomically distant blood-seeking predators, Stable fly and Wolf, while evoking avoidance responses in the prey species Mouse. We extend this by demonstrating that this chemical cue is preserved in humans as well; E2D induces postural avoidance, increases physiological arousal, and enhances visual perception of affective stimuli. This is the first demonstration of a single chemical cue with the dual function of guiding both approach and avoidance in a predator-prey predicted manner across taxonomically distant species, as well as the first known chemosignal that affects both human and non-human animals alike

Discovery of novel potent ΔF508-CFTR correctors that target the nucleotide binding domain

International audienceThe deletion of Phe508 (ΔF508) in the first nucleotide binding domain (NBD1) of CFTR is the most common mutation associated with cystic fibrosis. The ΔF508-CFTR mutant is recognized as improperly folded and targeted for proteasomal degradation. Based on molecular dynamics simulation results, we hypothesized that interaction between ΔF508-NBD1 and housekeeping proteins prevents ΔF508-CFTR delivery to the plasma membrane. Based on this assumption we applied structure-based virtual screening to identify new low-molecular-weight compounds that should bind to ΔF508-NBD1 and act as protein-protein interaction inhibitors. Using different functional assays for CFTR activity, we demonstrated that in silico-selected compounds induced functional expression of ΔF508-CFTR in transfected HeLa cells, human bronchial CF cells in primary culture, and in the nasal epithelium of homozygous ΔF508-CFTR mice. The proposed compounds disrupt keratin8-ΔF508-CFTR interaction in ΔF508-CFTR HeLa cells. Structural analysis of ΔF508-NBD1 in the presence of these compounds suggests their binding to NBD1. We conclude that our strategy leads to the discovery of new compounds that are among the most potent correctors of ΔF508-CFTR trafficking defect known to date