Biology subjects

Levin, E.

Publications and source records attributed to Levin, E..

8 recordsLinked to original sources

bioRxiv2025

Pentilludin reduces rat amphetamine and remifentail self-administration with good pharmacologic and toxicologic profiles

Pentilludin is a novel, potent (690 nM) irreversible inhibitor of actions of the receptor type protein tyrosine phosphatase D (PTPRD). Pentilludin displays no in vitro activities in Ames or micronucleus tests, at hERG channels or at targets for currently-licensed drugs. Rats treated with pentilludin doses up to 100 mg/kg/day for two weeks have not been found to display behavioral, hematologic or serum chemistry abnormalities. Treatment with 20 mg/kg sc pentilludin prior to every other M-W-F self-administration session substantially reduces self-administration of amphetamine and more modestly reduces self-administration of remifentanil. Pentilludin provides a novel means for reducing self-administration of psychostimulant and, modestly, opiate drugs in ways that could enhance abstinence in humans.

pharmacology and toxicology↗

bioRxiv2023

Autophagy Restricts Tomato Fruit Ripening Via a General Role in Ethylene Repression

Autophagy, a cellular degradation pathway, and the phytohormone ethylene function in plant development, senescence, and stress responses. However, the manner of their interaction is mostly unknown. We reasoned that this may be revealed by studying autophagy in a climacteric fruit ripening context, for which ethylene is crucial. During ripening, fruits undergo softening, color change, toxic compound degradation, volatile production, and sugar assembly by fine-tuning synthesis and degradation of their cellular content. For autophagy activity assessment, we analyzed autophagy-related 8 (ATG8) lipidation and GFP-ATG8-labeled autophagosome flux in tomato fruit cells. Autophagy activity increased sharply from ripening initiation, climaxed at its middle stage, and declined towards its end, resembling ethylene production dynamics. Silencing the core-autophagy genes SlATG2, SlATG7, and SlATG4 separately in mature fruits resulted in early ethylene production and ripening onset, which was abrogated by 1-methylcyclopropene (1-MCP), an ethylene signaling inhibitor. Beyond ripening, Arabidopsis atg5 and atg7 mutant seedlings exhibited elevated ethylene production and sensitivity to 1-Aminocyclopropane 1-carboxylic acid (ACC), ethylenes precursor, which induces autophagy. This research demonstrates that autophagy limits tomato fruit ripening via a general role in ethylene restriction, opening the path for a mechanistic understanding of autophagy-ethylene crosstalk and harnessing autophagy for fruit shelf-life extension.

plant biology↗

bioRxiv2023

An experimental approach towards untangling the role of nature versus nurture in shaping the microbiome of social insects

The gut microbiota is intimately related to host wellbeing, in terms of physiology, immune function, and even social interactions. The strength of this relationship is dynamic, but the extent to which the microbiome is shaped by the identity of the host (nature) or its environment (nurture) remains largely unknown. Here we aimed to identify factors shaping the microbiomes of nursing workers and larvae of two Vespidae species, using a cross-species experimental design to control for effects of environment, host identity and their interactions. We found that the microbiome composition of adults depended principally on the environment. Conversely, larval microbiome composition differed more between host species, regardless of treatment. We also found distinct microbiota profiles between the two species, across life stages and independently. These findings further elucidate the complexity of the host-microbiome relationship shaped by the environment while retaining symbionts that benefit the host. These results suggest that holobiont evolution may have promoted the rise of social behavior in animals.

evolutionary biology↗

bioRxiv2022

Long-term temporal stability of peripheral blood DNA methylation alterations in patients with inflammatory bowel disease.

IntroductionThere is great current interest in the potential application of DNA methylation alterations in peripheral blood leukocytes (PBL) as biomarkers of susceptibility, progression and treatment response in inflammatory bowel disease (IBD). However, the intra-individual stability of PBL methylation in IBD has not been characterised. Here, we studied the long-term stability of all probes located on the Illumina HumanMethylation EPIC BeadChip array. MethodsWe followed a cohort of 46 adult IBD patients (36 Crohns disease (CD), 10 ulcerative colitis (UC), median age 44 (IQR: 27-56), 50% female) that received standard care without any intervention at the Amsterdam UMC. Paired PBL samples were collected at two time points with a median 7 (range: 2-9) years in between. Differential methylation and intra-class correlation (ICC) analyses were used to identify time-associated differences and temporally stable CpGs, respectively. ResultsAround 60% of all EPIC array loci presented poor intra-individual stability (ICC <0.50); 78.114 ({approx}9%) showed good (ICC 0.75 - 0.89); and 41.274 ({approx}5%) excellent (ICC [≥]0.90) stability. Focusing on previously identified consistently differentially methylated positions indicated that 22 CD-, 11 UC-, and 24 IBD-associated loci demonstrated high stability (ICC [≥]0.75) over time; of these, we observed a marked stability of CpG loci associated to the HLA genes. ConclusionOur data provide insight into the long-term stability of the PBL DNA methylome within an IBD context, facilitating the selection of biologically relevant and robust IBD-associated epigenetic biomarkers with increased potential for independent validation. These data also have potential implications in understanding disease pathogenesis.

genetics↗

bioRxiv2019

Population Health Genetic Screening for Tier 1 Inherited Diseases in Northern Nevada: 90% of At-Risk Carriers are Missed

In an unselected population of 23,713 participants who underwent clinical exome sequencing as a part of the Healthy Nevada Project (HNP) in Northern Nevada (Renown Health, Reno, Nevada) from March 15, 2018, to Sept 30, 2018 (Table S1) we find a 1.26% carrier rate for expected pathogenic and likely pathogenic genetic variants in (FH: LDLR, PCSK9, APOB), Hereditary Breast and Ovarian Cancer (HBOC: BRCA1, BRCA2) and Lynch Syndrome (LS: MLH1, MSH2, MSH6, PSM2) with over 90% of carriers undetected under current medical practice. 26% of carriers were found to have advanced disease with 70% first diagnosed before the age of 65. Less than 20% of all carriers had any documented suspicion for inherited genetic disease in the medical record and upon direct follow-up survey under 40% of carriers had family history of relevant disease. A population preventative genetic screening approach for patients under 45 may improve outcomes.\n\nO_TBL View this table:\norg.highwire.dtl.DTLVardef@1eb1896org.highwire.dtl.DTLVardef@19b2a11org.highwire.dtl.DTLVardef@1e6da81org.highwire.dtl.DTLVardef@1138699org.highwire.dtl.DTLVardef@e9c415_HPS_FORMAT_FIGEXP M_TBL O_FLOATNOTable S1:C_FLOATNO O_TABLECAPTIONDemographic Profile of Healthy Nevada Project Participants.\n\nC_TABLECAPTION C_TBL

genetics↗

bioRxiv2018

Toward single particle reconstruction without particle picking: Breaking the detection limit

Single-particle cryo-electron microscopy (cryo-EM) has recently joined X-ray crystallography and NMR spectroscopy as a high-resolution structural method for biological macromolecules. In a cryo-EM experiment, the microscope produces images called micrographs. Projections of the molecule of interest are embedded in the micrographs at unknown locations, and under unknown viewing directions. Standard imaging techniques first locate these projections (detection) and then reconstruct the 3-D structure from them. Unfortunately, high noise levels hinder detection. When reliable detection is rendered impossible, the standard techniques fail. This is a problem especially for small molecules, which can be particularly hard to detect. In this paper, we propose a radically different approach: we contend that the structure could, in principle, be reconstructed directly from the micrographs, without intermediate detection. As a result, even small molecules should be within reach for cryo-EM. To support this claim, we setup a simplified mathematical model and demonstrate how our autocorrelation analysis technique allows to go directly from the micrographs to the sought signals. This involves only one pass over the micrographs, which is desirable for large experiments. We show numerical results and discuss challenges that lay ahead to turn this proof-of-concept into a competitive alternative to state-of-the-art algorithms.

molecular biology↗

bioRxiv2018

Reticulate Evolutionary History of a Western Palaearctic Bat Complex Explained by Multiple mtDNA Introgressions in Secondary Contacts

AimThere is increasing evidence showing that species within various taxonomic groups have reticulate evolutionary histories with several cases of introgression events. Investigating the phylogeography of species complexes can provide insight about the introgressions, when and where these hybridizations occurred. In this study, we investigate the biogeography of a widely distributed Western Palaearctic bat species complex, namely Myotis nattereri sensu lato. This complex exhibits high genetic diversity and in its western distribution range is composed of deeply diverged genetical lineages. However, little is known about the genetic structure of the eastern populations. We also infer the conservation and taxonomical implications of the identified genetic divergences.\n\nLocationWestern Palaearctic\n\nMethodsWe analyzed 175 specimens collected from 67 locations and sequenced one mitochondrial and four nuclear DNA markers, and combined these with the available Gen-Bank sequences. We used haplotype networks, PCA, t-SNE, and Bayesian clustering algorithms to investigate the population structure and Bayesian trees to infer the phylogenetic relationship of the lineages.\n\nMain conclusionsWe identified deeply divergent genetical lineages. In some cases, nuclear and mitochondrial markers were discordant, which we interpret are caused by hybridization between lineages. We identified three such introgression events. Our findings suggest that the M. nattereri complex has a reticulate evolutionary history with multiple cases of hybridizations between some of the identified lineages. We also suggest a revision in the taxonomy of this species group, with two possible new taxa: M. hoveli and M. tschuliensis.

evolutionary biology↗

bioRxiv2018

Knomics-Biota - a system for exploratory analysis of human gut microbiota data

SummaryMetagenomic surveys of human microbiota are becoming increasingly widespread in academic research as well as in food and pharmaceutical industries and clinical context. Intuitive tools for exploration of experimental data are of high interest to researchers. Knomics-Biota is a Web-based resource for exploratory analysis of human gut metagenomes. Users can generate analytical reports that correspond to common experimental schemes (like case-control study or paired comparison). Statistical analysis and visualizations of microbiota composition are provided in association with the external factors and in the context of thousands of publicly available datasets.\n\nAvailability and ImplementationThe Web-service is available at https://biota.knomics.ru.\n\nContactanna.popenko@knomics.ru or a.tyakht@gmail.com.\n\nSupplementary informationSupplementary figures are available at Bioinformatics online.

bioinformatics↗