Discovery of a New Natural Product and a Deactivation of a Quorum Sensing System by Culturing a “Producer” Bacterium With a Heat-Killed “Inducer” Culture

Herein we describe a modified bacterial culture methodology as a tool to discover new natural products via supplementing actinomycete fermentation media with autoclaved cultures of “inducer” microbes. Using seven actinomycetes and four inducer microbes, we detected 28 metabolites that were induced in UHPLC-HRESIMS-based analysis of bacterial fermentations. Metabolomic analysis indicated that each inducer elicited a unique response from the actinomycetes and that some chemical responses were specific to each inducer-producer combination. Among these 28 metabolites, hydrazidomycin D, a new hydrazide-containing natural product was isolated from the pair Streptomyces sp. RKBH-B178 and Mycobacterium smegmatis. This result validated the effectiveness of the strategy in discovering new natural products. From the same set of induced metabolites, an in-depth investigation of a fermentation of Streptomyces sp. RKBH-B178 and autoclaved Pseudomonas aeruginosa led to the discovery of a glucuronidated analog of the pseudomonas quinolone signal (PQS). We demonstrated that RKBH-B178 is able to biotransform the P. aeruginosa quorum sensing molecules, 2-heptyl-4-quinolone (HHQ), and PQS to form PQS-GlcA. Further, PQS-GlcA was shown to have poor binding affinity to PqsR, the innate receptor of HHQ and PQS

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

De novo variants in MPP5 cause global developmental delay and behavioral changes

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Comparison of acarological risk metrics derived from active and passive surveillance and their concordance with tick-borne disease incidence

Tick-borne diseases continue to threaten human health across the United States. Both active and passive tick surveillance can complement human case surveillance, providing spatio-temporal information on when and where humans are at risk for encounters with ticks and tick-borne pathogens. However, little work has been done to assess the concordance of the acarological risk metrics from each surveillance method. We used data on Ixodes scapularis and its associated human pathogens from Connecticut (2019–2021) collected through active collections (drag sampling) or passive submissions from the public to compare county estimates of tick and pathogen presence, infection prevalence, and tick abundance by life stage. Between the surveillance strategies, we found complete agreement in estimates of tick and pathogen presence, high concordance in infection prevalence estimates for Anaplasma phagocytophilum, Borrelia burgdorferi sensu stricto, and Babesia microti, but no consistent relationships between actively and passively derived estimates of tick abundance or abundance of infected ticks by life stage. We also compared nymphal metrics (i.e., pathogen prevalence in nymphs, nymphal abundance, and abundance of infected nymphs) with reported incidence of Lyme disease, anaplasmosis, and babesiosis, but did not find any consistent relationships with any of these metrics. The small spatial and temporal scale for which we had consistently collected active and passive data limited our ability to find significant relationships. Findings are likely to differ if examined across a broader spatial or temporal coverage with greater variation in acarological and epidemiological outcomes. Our results indicate similar outcomes between some actively and passively derived tick surveillance metrics (tick and pathogen presence, pathogen prevalence), but comparisons were variable for abundance estimates

SheepGenomics and the international sheep genomics consortium

SheepGenomics is a strategic investment by Meat & Livestock Australia and Australian Wool Innovation Limited and 11 Australian and New Zealand research organizations to deliver tangible outcomes from genomics research to the sheep industry. The overall strategy of SheepGenomics is to 'find useful genes and put them to work'. To achieve this has required the development of significant resources including a half-sib design mapping flock using over 16 industry sires and 4 sires from previous QTL studies to generate and extensively phenotype from 200 to 400 progeny/sire. The original intent was to genotype the progeny using a limited number of microsatellite markers and then fine-map selected progeny to discover genes for use in industry breeding programs and for further study. Development of genomic resources for sheep has proceeded to the stage where it is now becoming practical to genotype the progeny of the Sheep Genomics flock with tens of thousands of SNPs and use the outputs to derive genome selection derived breeding values (in addition to many new QTL). This change in strategy and deliverables would not have been possible without a substantial contribution from the International Sheep Genomics Consortium (ISGC) to develop sheep-specific genomic information in the public domain. The ISGC has been instrumental in developing a sheep BAC library, its end sequencing and alignment against other genomes. This has resulted in development of a virtual sheep genome, which in turn underpins current activities to discover and use tens of thousands of ordered sheep SNPs

Prefrontal cortex and flexible cognitive control: Rules without symbols

Human cognitive control is uniquely flexible and has been shown to depend on prefrontal cortex (PFC). But exactly how the biological mechanisms of the PFC support flexible cognitive control remains a profound mystery. Existing theoretical models have posited powerful task-specific PFC representations, but not how these develop. We show how this can occur when a set of PFC-specific neural mechanisms interact with breadth of experience to self organize abstract rule-like PFC representations that support flexible generalization in novel tasks. The same model is shown to apply to benchmark PFC tasks (Stroop and Wisconsin card sorting), accurately simulating the behavior of neurologically intact and frontally damaged people

Sex Chromosome Transformation and the Origin of a Male-Specific X Chromosome in the Creeping Vole.

The mammalian sex chromosome system (XX female/XY male) is ancient and highly conserved. The sex chromosome karyotype of the creeping vole (Microtus oregoni) represents a long-standing anomaly, with an X chromosome that is unpaired in females (X0) and exclusively maternally transmitted. We produced a highly contiguous male genome assembly, together with short-read genomes and transcriptomes for both sexes. We show that M. oregoni has lost an independently segregating Y chromosome and that the male-specific sex chromosome is a second X chromosome that is largely homologous to the maternally transmitted X. Both maternally inherited and male-specific sex chromosomes carry fragments of the ancestral Y chromosome. Consequences of this recently transformed sex chromosome system include Y-like degeneration and gene amplification on the male-specific X, expression of ancestral Y-linked genes in females, and X inactivation of the male-specific chromosome in male somatic cells. The genome of M. oregoni elucidates the processes that shape the gene content and dosage of mammalian sex chromosomes and exemplifies a rare case of plasticity in an ancient sex chromosome system

Differential adhesion regulates neurite placement via a retrograde zippering mechanism

© The Author(s), 2021. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Sengupta, T., Koonce, N. L., Vazquez-Martinez, N., Moyle, M. W., Duncan, L. H., Emerson, S. E., Han, X., Shao, L., Wu, Y., Santella, A., Fan, L., Bao, Z., Mohler, W. A., Shroff, H., & Colon-Ramos, D. A. Differential adhesion regulates neurite placement via a retrograde zippering mechanism. Elife, 10, (2021): e71171, https://doi.org/10.7554/eLife.71171.During development, neurites and synapses segregate into specific neighborhoods or layers within nerve bundles. The developmental programs guiding placement of neurites in specific layers, and hence their incorporation into specific circuits, are not well understood. We implement novel imaging methods and quantitative models to document the embryonic development of the C. elegans brain neuropil, and discover that differential adhesion mechanisms control precise placement of single neurites onto specific layers. Differential adhesion is orchestrated via developmentally regulated expression of the IgCAM SYG-1, and its partner ligand SYG-2. Changes in SYG-1 expression across neuropil layers result in changes in adhesive forces, which sort SYG-2-expressing neurons. Sorting to layers occurs, not via outgrowth from the neurite tip, but via an alternate mechanism of retrograde zippering, involving interactions between neurite shafts. Our study indicates that biophysical principles from differential adhesion govern neurite placement and synaptic specificity in vivo in developing neuropil bundles.National Institutes of Health (R24-OD01647) Zhirong Bao William Mohler Daniel A Colón-Ramos National Institutes of Health (R01NS076558) Daniel A Colón-Ramos National Institutes of Health (DP1NS111778) Daniel A Colón-Ramos Howard Hughes Medical Institute (Faculty Scholar Award) Daniel A Colón-Ramos Marine Biological Laboratory (Whitman and Fellows program) Hari Shroff Daniel A Colón-Ramos Gordon and Betty Moore Foundation (Moore Grant) Hari Shroff Daniel A Colón-Ramos Gruber Foundation (Gruber Science Fellowship) Titas Sengupta National Institutes of Health (Predoctoral Training Program in Genetics NIH 2020 T32 GM.) Noelle L Koonce National Institutes of Health (F32-NS098616) Mark W Moyle National Institutes of Health (NIBIB Intramural Research Program) Hari Shroff National Institutes of Health (P30CA008748) Zhirong Ba