Laura Karpauskaite

New York University Abu Dhabi

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Mazin Magzoub

New York University Abu Dhabi

Sunil Kumar

University of Denver

Andrew D. Hamilton

Yale University

Debabrata Maity

Indian Institute of Chemical Technology

Liaqat Ali

Xi'an Technological University

Mona Kalmouni

New York University Abu Dhabi

Gennaro Esposito

Istituto Nazionale Biostrutture e Biosistemi

Sarah Hassan

Imperial College London

L. Palanikumar

New York University Abu Dhabi

Ibrahim Chehade

New York University Abu Dhabi

Cooperative Institutions

Chinese Academy of Sciences

Zhejiang University

University of Chinese Academy of Sciences

Tecnológico de Monterrey

University of Oxford

Sun Yat-sen University

Shanghai Jiao Tong University

Sichuan University

Fudan University

Peking University

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Robust estimation of bacterial cell count from optical density

Communications Biology (2020)

Jacob Beal Natalie G. Farny Traci Haddock-Angelli Vinoo Selvarajah Geoff Baldwin

Abstract Optical density (OD) is widely used to estimate the density of cells in liquid culture, but cannot be compared between instruments without a standardized calibration protocol and is challenging to relate to actual cell count. We address this with an interlaboratory study comparing three simple, low-cost, and highly accessible OD calibration protocols across 244 laboratories, applied to eight strains of constitutive GFP-expressing E. coli . Based on our results, we recommend calibrating OD to estimated cell count using serial dilution of silica microspheres, which produces highly precise calibration (95.5% of residuals <1.2-fold), is easily assessed for quality control, also assesses instrument effective linear range, and can be combined with fluorescence calibration to obtain units of Molecules of Equivalent Fluorescein (MEFL) per cell, allowing direct comparison and data fusion with flow cytometry measurements: in our study, fluorescence per cell measurements showed only a 1.07-fold mean difference between plate reader and flow cytometry data.

Optical density

Dilution

Plate count

10.1038/s42003-020-01127-5

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Citations (147)

Protein mimetic amyloid inhibitor potently abrogates cancer-associated mutant p53 aggregation and restores tumor suppressor function

Nature Communications (2021)

L. Palanikumar Laura Karpauskaite Mohamed Al‐Sayegh Ibrahim Chehade Maheen Alam

Abstract Missense mutations in p53 are severely deleterious and occur in over 50% of all human cancers. The majority of these mutations are located in the inherently unstable DNA-binding domain (DBD), many of which destabilize the domain further and expose its aggregation-prone hydrophobic core, prompting self-assembly of mutant p53 into inactive cytosolic amyloid-like aggregates. Screening an oligopyridylamide library, previously shown to inhibit amyloid formation associated with Alzheimer’s disease and type II diabetes, identified a tripyridylamide, ADH-6, that abrogates self-assembly of the aggregation-nucleating subdomain of mutant p53 DBD. Moreover, ADH-6 targets and dissociates mutant p53 aggregates in human cancer cells, which restores p53’s transcriptional activity, leading to cell cycle arrest and apoptosis. Notably, ADH-6 treatment effectively shrinks xenografts harboring mutant p53, while exhibiting no toxicity to healthy tissue, thereby substantially prolonging survival. This study demonstrates the successful application of a bona fide small-molecule amyloid inhibitor as a potent anticancer agent.

Amyloid (mycology)

Loss function

10.1038/s41467-021-23985-1

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Citations (86)

Protein mimetic amyloid inhibitor potently abrogates cancer-associated mutant p53 aggregation and restores tumor suppressor function

bioRxiv (Cold Spring Harbor Laboratory) (2020)

L. Palanikumar Laura Karpauskaite Sarah Hassan Maheen Alam Mohamed Al‐Sayegh

ABSTRACT Missense mutations in p53 are severely deleterious and occur in over 50% of all human cancers. The vast majority of these mutations are located in the inherently unstable DNA-binding domain (DBD), many of which destabilize the domain further and expose its aggregation-prone hydrophobic core, prompting self-assembly of mutant p53 into inactive cytosolic amyloid-like aggregates. Screening an oligopyridylamide library, previously shown to inhibit amyloid formation associated with Alzheimer’s disease and type II diabetes, identified a tripyridylamide, ADH-6, that potently abrogates self-assembly of the aggregation-nucleating subdomain of mutant p53 DBD. Moreover, ADH-6 effectively targets and dissociates mutant p53 aggregates in human cancer cells, which restores p53’s transcriptional activity, leading to cell cycle arrest and apoptosis. Notably, ADH-6 treatment substantially shrinks xenografts harboring mutant p53 and prolongs survival, while exhibiting no toxicity to healthy tissue. This study demonstrates the first successful application of a bona fide small-molecule amyloid inhibitor as an anticancer agent.

Amyloid (mycology)

10.1101/2020.08.10.243154

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Author Correction: Robust estimation of bacterial cell count from optical density

Communications Biology (2020)

Jacob Beal Natalie G. Farny Traci Haddock-Angelli Vinoo Selvarajah Geoff Baldwin

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Amendment

Optical density

10.1038/s42003-020-01371-9

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Citations (10)

Oligopyridylamide-based protein mimetic inhibits cancer-associated mutant p53 amyloid-like aggregation and restores its tumor suppressor function

Biophysical Journal (2022)

L. Palanikumar Laura Karpauskaite Mohamed Al‐Sayegh Ibrahim Chehade Maheen Ali

P53 protein

Amyloid (mycology)

10.1016/j.bpj.2021.11.1253

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Sub-stoichiometric inhibition of IAPP aggregation: a peptidomimetic approach to anti-amyloid agents

RSC Chemical Biology (2020)

Debabrata Maity Sunil Kumar Ruyof AlHussein Lothar Gremer Madeline Howarth

Naphthalimide-appended oligopyridylamide peptidomimetic modulate islet amyloid polypeptide amyloidogenesis and disaggregate preformed oligomers and fibrils into non-toxic conformations at substoichiometric concentration.

Peptidomimetic

Amyloid (mycology)

Stoichiometry

10.1039/d0cb00086h

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Citations (20)

The human ribosome modulates multidomain protein biogenesis by delaying cotranslational domain docking

bioRxiv (Cold Spring Harbor Laboratory) (2024)

Grant A. Pellowe Tomas B. Voisin Laura Karpauskaite Sarah Maslen Alžběta Roeselová

Proteins with multiple domains are intrinsically prone to misfold, yet fold efficiently during their synthesis on the ribosome. This is especially important in eukaryotes, where multidomain proteins predominate. Here, we sought to understand how multidomain protein folding is modulated by the eukaryotic ribosome. We used cryo-electron microscopy and hydrogen/deuterium exchange-mass spectrometry to characterise the structure and dynamics of partially-synthesised intermediates of a model multidomain protein. We find that nascent subdomains fold progressively during synthesis on the human ribosome, templated by interactions across domain interfaces. The conformational ensemble of the nascent chain is tuned by its unstructured C-terminal segments, which keep interfaces between folded domains in dynamic equilibrium until translation termination. This contrasts with the bacterial ribosome, on which domain interfaces form early and remain stable during synthesis. Delayed domain docking may avoid interdomain misfolding to promote the maturation of multidomain proteins in eukaryotes.

Docking (animal)

ribosome biogenesis

10.1101/2024.09.19.613857

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