Biology subjects

Weiner, S.

Publications and source records attributed to Weiner, S..

9 recordsLinked to original sources

bioRxiv2026

Optimizing copy number profiles for tumor cell phylogeny inference from low-coverage single-cell sequencing data

Motivation: Accurate reconstruction of tumor cell phylogenies is crucial for understanding cancer evolutionary dynamics, inferring intra-tumor heterogeneity, and designing effective and personalized cancer treatment strategies. One of the most promising and cost-effective approaches for reconstructing tumor phylogenies for large numbers of cells is to use copy number alteration (CNA) data obtained from low-coverage single-cell DNA sequencing of sampled tumor cells. However, error and uncertainty in inferred copy number profiles (CNPs), resulting from low sequence coverage, can have a drastic negative effect on the reconstruction accuracy of tumor cell phylogenies. Results: In this work, we show that careful selection of bin size, a critical tuning parameter for inferring CNPs, is necessary to maximize the accuracy of tumor cell phylogeny inference. Specifically, we (i) use three previously published low-coverage single-cell DNA sequencing datasets from real tumors to demonstrate that even small changes in bin size can have a drastic impact on downstream tumor phylogeny reconstruction, (ii) show that this effect persists even when using simulated low-coverage datasets generated under idealized conditions with minimal noise, and (iii) propose a simple computational approach to select bin sizes that maximize tumor phylogeny accuracy. Our experiments span a wide range of bin sizes and account for the impact of various factors including coverage-level, phylogeny reconstruction method, and CNP inference method, and explicitly account for phylogenetic reconstruction uncertainty. Our evaluation of the proposed computational approach for bin size selection shows that it can significantly improve tumor cell phylogeny reconstruction accuracy compared to baseline methods. Availability: Freely available from https://github.com/Tanveer14/BinSelector.

bioinformatics↗

bioRxiv2025

Maternal low-fat and high-fat diet decreases survival and alters cytokine signaling in neonatal mice with Staphylococcus epidermidis sepsis

ObjectiveMaternal malnutrition increases susceptibility to sepsis and mortality in neonates. The reason for this increased susceptibility remains unknown. We aimed to evaluate bacterial burden and serum cytokine levels in septic neonatal mice born to dams with malnutrition. Methods6-week-old C57BL/6 dams were placed on a low-fat (LFD) (10% kcal from fat), control (CD) (18% kcal from fat), or high-fat (HFD) (60% kcal from fat) diet for 3 weeks prior to breeding. Sepsis was induced in P4-P6 offspring via intraperitoneal Staphylococcus epidermidis injection. Mice were monitored for survival. At 12h after sepsis, serum and peritoneal wash fluid were collected for bacterial count and serum cytokine levels. In the absence of infection, P4-P6 offspring had untargeted serum metabolomics performed. ResultsSeptic offspring of dams fed LFD and HFD had significantly higher mortality than offspring of dams fed CD. There was no difference in serum or peritoneal wash bacterial loads. Maternal diet and Staphylococcus epidermidis sepsis caused changes in basal serum cytokine levels, with HFD causing decreased cytokine elevation during sepsis. Maternal LFD and HFD altered similar metabolomic pathways in offspring. ConclusionMaternal LFD and HFD decrease survival during neonatal sepsis and alter serum cytokines and the metabolome, supporting a role for maternal nutrition in neonatal immune function and infection susceptibility.

immunology↗

bioRxiv2024

A systematic assessment of phylogenomic approaches for microbial species tree reconstruction

A key challenge in microbial phylogenomics is that microbial gene families are often affected by extensive horizontal gene transfer (HGT). As a result, most existing methods for microbial phylogenomics can only make use of a small subset of the gene families present in the microbial genomes under consideration, potentially biasing their results and affecting their accuracy. To address this challenge, several methods have recently been developed for inferring microbial species trees from genome-scale datasets of gene families affected by evolutionary events such as HGT, gene duplication, and gene loss. In this work, we use extensive simulated and real biological datasets to systematically assess the accuracies of four recently developed methods for microbial phylogenomics, SpeciesRax, ASTRAL-Pro 2, PhyloGTP, and AleRax, under a range of different conditions. Our analysis reveals important insights into the relative performance of these methods on datasets with different characteristics, identifies shared weaknesses when analyzing complex biological datasets, and demonstrates the importance of accounting for gene tree inference error/uncertainty for improved species tree reconstruction. Among other results, we find that (i) AleRax, the only method that explicitly accounts for gene tree inference error/uncertainty, shows the best species tree reconstruction accuracy among all tested methods, (ii) PhyloGTP (developed previously by the authors of this paper) shows the best overall accuracy among methods that do not account for gene tree error and uncertainty, (iii) ASTRAL-Pro 2 is less accurate than the other methods across nearly all tested conditions, and (iv) explicitly accounting for gene tree inference error/uncertainty can lead to substantial improvements in species tree reconstruction accuracy. Importantly, we also find that all methods, including AleRax and PhyloGTP, are susceptible to biases present in complex real biological datasets and can sometimes yield misleading phylogenies.

bioinformatics↗

bioRxiv2024

DICE: Fast and Accurate Distance-Based Reconstruction of Single-Cell Copy Number Phylogenies

Somatic copy number alterations (sCNAs) are valuable phylogenetic markers for inferring evolutionary relationships among tumor cell subpopulations. Advances in single-cell DNA sequencing technologies are making it possible to obtain such sCNAs datasets at ever-larger scales. However, existing methods for reconstructing phylogenies from sCNAs are often too slow for large datasets. Moreover, the accuracies of many existing methods are highly sensitive to error and other features of the analyzed datasets. In this work, we propose two new distance-based approaches for reconstructing single-cell tumor phylogenies from sCNA data. The new methods, DICE-bar and DICE-star, are based on novel, easy-to-compute distance measures and drastically outperform the current state-of-the-art in terms of both accuracy and scalability. Using carefully simulated datasets, we find that DICE-bar and DICE-star significantly improve upon the accuracies of existing methods across a wide range of experimental conditions and error rates while simultaneously being orders of magnitude faster. Our experimental analysis also reveals how noise/error in copy number inference, as expected for real datasets, can drastically impact the accuracies of many existing methods. We apply DICE-star, the most accurate method on error-prone datasets, to two real single-cell breast cancer datasets and find that it helps identify previously unreported rare cell populations.

bioinformatics↗

bioRxiv2022

The petrous bone contains high concentrations of osteocytes: one possible reason why ancient DNA is better preserved in this bone.

The characterization of ancient DNA in fossil bones is providing invaluable information on the genetics of past human and other animal populations. These studies have been aided enormously by the discovery that ancient DNA is relatively well preserved in the petrous bone compared to most other bones. The reasons for this better preservation are however not well understood. Here we examine the hypothesis that one reason for better DNA preservation in the petrous bone is that fresh petrous bone contains more DNA than other bones. We therefore determined the concentrations of osteocyte cells occluded inside lacunae within the petrous bone and compared these concentrations to other bones from the domestic pig using high resolution microCT. We show that the concentrations of osteocyte lacunae in the inner layer of the pig petrous bone adjacent to the otic chamber are about three times higher than in the temporal bone, as well as the cortical bone of the femur. The sizes and shapes of the lacuna in the inner layer of the petrous bone are similar to those in the femur. We also confirm that the petrous bone lacunae do contain osteocytes using a histological stain for DNA. We therefore conclude that one possible reason for better preservation of ancient DNA in the petrous bone is that this bone initially contains up to three times more DNA than other bones, and hence during diagenesis more DNA is likely to be preserved. We also note that the osteocytes in the inner layer of the petrous bone may have a function in hearing.

zoology↗

bioRxiv2020

Cellular pathways of calcium transport and concentration towards mineral formation in sea urchin larvae

Sea urchin larvae have an endoskeleton consisting of two calcitic spicules. The primary mesenchyme cells (PMCs) are the cells that are responsible for spicule formation. PMCs endocytose sea water from the larval internal body cavity into a network of vacuoles and vesicles, where calcium ions are concentrated until they precipitate in the form of amorphous calcium carbonate (ACC). The mineral is subsequently transferred to the syncytium, where the spicule forms. Using cryo-soft X-ray microscopy (cryo-SXM) we imaged intra-cellular calcium-containing particles in the PMCs and acquired Ca-L2,3 X-ray absorption near edge spectra (XANES) of these Ca-particles. Using the pre-peak/main peak (L2/ L2) intensity ratio, which reflects the atomic order in the first Ca coordination shell, we determined the state of the calcium ions in each particle. The concentration of Ca in each of the particles was also determined by the integrated area in the main Ca absorption peak. We observed about 700 Ca-particles with order parameters, L2/ L2, ranging from solution to hydrated and anhydrous ACC, and with concentrations ranging between 1-15 M. We conclude that in each cell the calcium ions exist in a continuum of states. This implies that most, but not all water, is expelled from the particles. This cellular process of calcium concentration may represent a widespread pathway in mineralizing organisms. SignificanceOrganisms form mineralized skeletons, many of which are composed of calcium salts. Marine organisms extract calcium ions from sea water. One of the main unresolved issues is how organisms concentrate calcium by more than 3 orders of magnitude, to achieve mineral deposition in their skeleton. Here we determine the calcium state in each of the calcium-containing vesicles inside the spicule-building cells of sea urchin larvae. We show that within one cell there is a wide range of concentrations and states from solution to solid. We hypothesize that calcium concentration increases gradually in each vesicle, starting from sea water levels and until mineral is deposited. This model might well be relevant to other phyla, thus advancing the understanding of biomineralization processes.

biophysics↗

bioRxiv2020

Cystoliths in Ficus leaves: increasing carbon fixation in saturating light by light scattering off a mineral substrate

The manner in which leaves adapt to different light intensities is key for enabling plants to survive in diverse environments and in constantly changing conditions. Many studies have addressed this subject, but little attention has been given to the effect that mineral deposits in leaves can have on photosynthesis. Here we study 6 species of Ficus and investigate how different cystolith configurations affect photosynthesis in both non-saturating and saturating light. We quantified the effect of light scattering by cystoliths on light absorption by measuring chlorophyll fluorescence intensity using microfluorimetry. We complement this by carbon assimilation measurements to directly estimate how light scattering by cystoliths affects the overall photosynthetic process. We show that light waste is reduced when irradiance is on a cystolith compared to cystolith free tissue. Moreover, light is channeled into the center of the leaf where photosynthesis occurs more efficiently than in the outer layers. This, in turn, leads to more efficient CO2 assimilation. We conclude that cystoliths contribute to photosynthesis optimization under saturating light. Cystoliths reduce the wasted portion of absorbed light under saturating irradiance by scattering light into the light-deprived leaf center. The increased efficiency may well provide important benefits to plants that form mineral scatterers.

plant biology↗

bioRxiv2017

Isoxanthopterin: An Optically Functional Biogenic Crystal in the Eyes of Decapod Crustaceans

The eyes of some aquatic animals form images through reflective optics. Shrimp, lobsters, crayfish and prawns possess reflecting superposition compound eyes, composed of thousands of square-faceted eye-units (ommatidia). Mirrors in the upper part of the eye (the distal mirror) reflect light collected from many ommatidia onto the underlying photosensitive elements of the retina, the rhabdoms. A second reflector, the tapetum, underlying the retina, back-scatters dispersed light onto the rhabdoms. Using microCT and cryo-SEM imaging accompanied by in situ micro-X-ray diffraction and micro-Raman spectroscopy, we investigated the hierarchical organization and materials properties of the reflective systems at high resolution and under close to physiological conditions. We show that the distal mirror consists of three or four layers of sparse plate-like nano-crystals. The tapetum is a diffuse reflector composed of hollow nanoparticles constructed from concentric lamellae of crystals. Isoxanthopterin, a pteridine analog of guanine, forms both the reflectors in the distal mirror and in the tapetum. The crystal structure of isoxanthopterin was determined from crystal structure prediction calculations and verified by comparison with experimental X-ray diffraction. The extended hydrogen bonded layers of the molecules results in an extremely high calculated refractive index in the H-bonded plane, n = 1.96, which makes isoxanthopterin crystals an ideal reflecting material. The crystal structure of isoxanthopterin, together with a detailed knowledge of the reflector superstructures, provide a rationalization of the reflective optics of the crustacean eye.\n\nSignificanceAquatic animals use reflectors in their eyes either to form images or to increase photon capture. Guanine is the most widespread molecular component of these reflectors. Here we show that crystals of isoxanthopterin, a pteridine analogue of guanine, form both the image-forming distal mirror and the intensity-enhancing tapetum reflector in the compound eyes of some decapod crustaceans. The crystal structure of isoxanthopterin was determined, providing an explanation for why these crystals are so well suited for efficient reflection. Pteridines were previously known only as pigments and our discovery raises the question of which other organic molecules may be used to form crystals with superior reflective properties either in organisms or in artificial optical devices.

bioengineering↗

bioRxiv2017

Demonstration of de novo chemotaxis in E. coli using a real-time, quantitative, and digital-like approach

Chemotaxis is the movement of an organism in response to an external chemical stimulus. This system enables bacteria to sense their immediate environment and adapt to changes in its chemical composition. Bacterial chemotaxis is mediated by chemoreceptors, membrane proteins that bind an effector and transduce the signal to the downstream proteins. From a synthetic biology perspective, the natural chemotactic repertoire is of little use since bacterial chemoreceptors have evolved to sense specific ligands that either benefit or harm the cell. Here we demonstrate that using a combined computational design approach together with a quantitative, real-time, and digital detection approach, we can rapidly design, manufacture, and characterize a synthetic chemoreceptor in E. coli for histamine (a ligand for which there are no known chemoreceptors). First, we employed a computational protocol that uses the Rosetta bioinformatics software together with high threshold filters to design mutational variants to the native Tar ligand binding domain that target histamine. Second, we tested different ligand-chemoreceptors pairs with a novel chemotaxis assay, based on optical reflectance interferometry of porous silicon (PSi) optical transducers, enabling label-free quantification of chemotaxis by monitoring real-time changes in the optical readout (expressed as the effective optical thickness, EOT). We found that different ligands can be characterized by an individual set of fingerprints in our assay. Namely, a binary, digital-like response in EOT change (i.e. positive or negative) that differentiates between attractants and repellants, the amplitude of change of EOT response, and the rate by which steady state in EOT change is reached. Using this assay, we were able to positively identify and characterize a single mutational chemoreceptor variant for histamine that mediated chemotaxis comparably to the natural Tar-aspartate system. Our results demonstrate the possibility of not only expanding the natural chemotaxis repertoire, but also provide a new quantitative assay by which to characterize the efficacy of the chemotactic response.

synthetic biology↗