bluuebunny/crossref_metadata_2025 huggingface dataset:
An integrative characterisation of prolinecisandtransconformers in a disordered peptide
Authors: Pettitt Alice J. , Shukla Vaibhav Kumar , Figueiredo Angelo Miguel , Newton Lydia S. , McCarthy Stephen , Tabor Alethea B. , Heller Gabriella T. , Lorenz Christian D. , Hansen D. Flemming
Published: May 2024

Intrinsically disordered proteins (IDPs) often contain proline residues, which undergocis/transisomerisation. While molecular dynamics (MD) simulations have the potential to fully characterise the prolinecisandtranssub-ensembles, they are limited by the slow timescales of isomerisation and force field inaccuracies. Nuclear magnetic resonance (NMR) spectroscopy can report on ensemble-averaged observables for both thecisandtransproline states, but a full atomistic characterisation of these sub-ensembles is challenging. Given the importance of prolinecis/transisomerisation for influencing the conformational sampling of disordered proteins, we employed a combination of all-atom MD simulations with enhanced sampling (metadynamics), NMR, and small-angle X-ray scattering (SAXS) to characterise the two sub-ensembles of the ORF6 C-terminal region (ORF6CTR) from SARS-CoV-2 corresponding to the proline-57 (P57)cisandtransstates. We performed MD simulations in three distinct force fields: AMBER03ws, AMBER99SB-disp, and CHARMM36m, which are all optimised for disordered proteins. Each simulation was run for an accumulated time of 180-220 µs until convergence was reached, as assessed by blocking analysis. A good agreement between thecis-P57 populations predicted from metadynamics simulations in AMBER03ws was observed with populations obtained from experimental NMR data. Moreover, we observed good agreement between the radius of gyration predicted from the metadynamics simulations in AMBER03ws and that measured using SAXS. Our findings suggest that both thecis-P57 andtrans-P57 conformations of ORF6CTRare extremely dynamic and that interdisciplinary approaches combining both multi-scale computations and experiments offer avenues to explore highly dynamic states that cannot be reliably characterised by either approach in isolation.

SIGNIFICANCE

This study employs MD simulations (with metadynamics), NMR spectroscopy, and SAXS to elucidate the individualcisandtransproline conformations of ORF6CTRfrom SARS-CoV-2. The good agreement on prolinecis/transpopulations observed in experiments (NMR) and those calculated from simulations in the AMBER03ws force field (with SAXS reweighting) showcases the efficiency of this interdisciplinary approach, which can be used to characterise highly dynamic disordered protein states, even for very slow processes. Furthermore, our study emphasises the importance of considering both computational and experimental methodologies to gain a more holistic understanding of highly dynamic proteins. The presented integrative approach sets a precedent for future studies aiming to explore complex and dynamic biological systems with slow transitions such as proline isomerisations.
Automated adjustment of metabolic niches enables the control of natural and engineered microbial co-cultures
Authors: Martinez Juan Andres , Bouchat Romain , Gallet de Saint Aurin Tiphaine , Martínez Luz María , Caspeta Luis , Telek Samuel , Zicler Andrew , Gosset Guillermo , Delvigne Frank
Published: May 2024

A lot of attention has been given to the understanding of microbial interactions leading to stable co-cultures, but the resulting technologies have been rarely challenged in dynamic cultivation conditions. In this work, substrate pulsing was performed to promote better control of the metabolic niches corresponding to each species, leading to the continuous co-cultivation of diverse microbial organisms. For this purpose, we used a cell-machine interface relying on automated flow cytometry, allowing to adjust the temporal profile of two metabolic niches according to a rhythm ensuring the successive growth of two species i.e., in our case a yeast and a bacterium. The resulting approach, called Automated Adjustment of Metabolic Niches (AAMN), was successfully employed for stabilizing both cooperative and competitive co-cultures. Additionally, AAMN can be considered as an enabling technology for the deployment of co-cultures in bioprocesses, demonstrated here based on the continuous bioproduction of p-coumaric acid. Taken altogether, the data accumulated suggest that AAMN could be used for a wider range of biological systems, but also to gain fundamental insights about microbial interaction mechanisms.
Naphthalimide-based, Single-Chromophore, Ratiometric Fluorescent Sensor for Tracking Intracellular pH
Authors: Das Sujit Kumar , Kahali Smitaroopa , Kar Sabnam , Madhavan Nandita , Datta Ankona
Published: May 2024

We report a novel, reversible, cell-permeable, pH-sensor, TRapH. TRapH afforded a pH-sensitive ratiometric emission response in the pH range ∼3-6, enabling imaging and quantification of pH in living cells. The biological-applicability of TRapH was illustrated via live-tracking of intracellular pH dynamics in living mammalian cells induced by a synthetic H+-transporter.
Predictive Control of Musculotendon Loads Across Fast and Slow-twitch Muscles in a Simulated System with Parallel Actuation
Authors: Nabipour Mahdi , Sawicki Gregory S. , Sartori Massimo
Published: May 2024

Research in lower limb wearable robotic control have largely focused on reducing the metabolic cost of walking or compensating for a portion of the biological joint torque e.g., by applying support proportional to estimated biological joint torques. However, due to different musculotendon unit (MTU) contractile speed properties, less attention has been given to the development of wearable robotic controllers that can steer MTU dynamics directly. Therefore, closed-loop control of MTU dynamics needs to be robust across fiber phenotypes, i.e. ranging from slow type I to fast type IIx in humans. The ability to closed-loop control the in-vivo dynamics of MTUs, could lead to a new class of wearable robots that can provide precise support to targeted MTUs, for preventing onset of injury or to provide precision rehabilitation to selected damaged tissues. In this paper, we introduce a novel closed-loop control framework that utilizes Nonlinear Model Predictive Control (NMPC) to keep the peak Achilles tendon force within predetermined boundaries during diverse range of cyclic force production simulations in the human ankle plantarflexors. This control framework employs a computationally efficient model comprising a modified Hill-type MTU contraction dynamics component and a model of the ankle joint with parallel actuation. Results indicate that the closed-form muscle-actuation model’s computational time is in the order of microseconds and is robust to different muscle contraction velocity properties. Furthermore, the controller achieves tendon force control within a timeframe below 14ms, aligning with the physiological electromechanical delay of the MTU and facilitating its potential for future real-world applications.
Roles of dimeric intermediates in RNA-catalyzed rolling circle synthesis
Authors: Kristoffersen Emil Laust , McRae Ewan K. , Sørensen Niels R. , Holliger Philipp , Andersen Ebbe S.
Published: May 2024

The RNA world hypothesis is supported by the discovery of RNA polymerase ribozymes that can perform RNA-catalyzed RNA replication processes on different RNA templates. Recently, RNA-catalyzed rolling circle synthesis (RCS) on small circular RNA (scRNA) templates has been demonstrated. However, the structural and dynamic properties of scRNA replication and its products and intermediates have never been explored. Here we have used cryogenic electron microscopy (cryo-EM) to characterize products and intermediates relevant for RCS replication and find that these form an unexpectedly diverse group of RNA nanostructures. The main structural motif observed is a fully hybridized dimeric complex composed of two scRNAs and their complement strands resolved to 5.3 Å. Cryo-EM also reveals higher order dimer filaments and dimer assembly intermediates suggesting a mechanism for assembly of the observed complexes. We show that the dimer complexes are stable and inhibit RNA-catalyzed RCS, but can be reactivated by addition of more scRNA templates. We propose that dimer formation may be a general property of RCS replication and speculate that the observed dimers might have benefited a primordial RNA genetic system by providing a stable “storage” form of RNA replication products and by coordinating RNA replication on both scRNA template strands.
ERK inhibits Cic repressor function via multisite phosphorylation
Authors: Paul Sayantanee , Ilkhani Khandan , Strozewski Nathan , Yang Liu , Denberg David W. , Christalin Wootchelmine , Shvartsman Stanislav Y. , Veraksa Alexey
Published: May 2024

The receptor tyrosine kinase (RTK)/Extracellular Signal-Regulated Kinase (ERK) signaling pathway controls cell proliferation, differentiation, and survival. How ERK activation is relayed to its phosphorylation targets is not well understood. The transcriptional repressor Capicua (Cic) has emerged as a key target for ERK-mediated downregulation inDrosophilaand mammals, and mutations in humanCICresult in cancer and neurological diseases. Phosphorylation by ERK is critical for Cic downregulation, but the identities of phosphosites inDrosophilaCic are unknown. Here, we identify sites of phosphorylation in Cic that are directly targeted by ERK and validate their developmental functions in vivo using mutant Cic variants. Cic phosphosites are distributed throughout the length of the protein, and a group of centrally located sites appears to have a primary role in Cic downregulation. Cic mutated in 20 high-confidence sites behaves as a “super-repressor” in vivo that is largely insensitive to ERK-mediated downregulation, despite fully retaining the ability to bind to ERK. No single site is sufficient to turn off Cic activity; instead, we find that ERK must phosphorylate multiple sites in Cic simultaneously to achieve full downregulation. This multisite phosphorylation likely targets phosphodegrons that are recognized by ubiquitin ligases such as Ago/FBXW7 and contributes to Cic degradation. This study advances our understanding of the molecular mechanisms of signal interpretation downstream of the RTK/ERK signaling network.
Enabling functionality and translation fidelity characterization of mRNA-based vaccines with a platform-based, antibody-free mass spectrometry detection approach
Authors: Stiving Alyssa Q. , Roose Benjamin W. , Tubbs Christopher , Haverick Mark , Gruber Ashley , Rustandi Richard R. , Kuiper Jesse , Schombs Matthew , Schuessler Hillary , Li Xuanwen
Published: May 2024

The success of mRNA-based therapeutics and vaccines can be attributed to their rapid development, adaptability to new disease variants, and scalable production. Modified ribonucleotides are often used in mRNA-based vaccines or therapeutics to enhance stability and reduce immunogenicity. However, substituting uridine with N1-methylpseudouridine has recently been shown to result in +1 ribosomal frameshifting that induces cellular immunity to the translated off-target protein. To accelerate vaccine development, it is critical to have analytical methods that can be rapidly brought online to assess the functionality and translation fidelity of mRNA constructs. Here, a platform-based, antibody-free method was developed using cell-free translation (CFT) and liquid chromatography-tandem mass spectrometry (MS) that can detect, characterize, and provide relative quantification of antigen proteins translated from mRNA vaccine drug substance. This workflow enabled the evaluation of mRNA subjected to thermal stress as well as bivalent (i.e., two mRNA encoding different antigen variants) drug substance. Additionally, the MS detection approach exhibited high sensitivity and specificity by accurately identifying all six translated proteins and their relative abundances in a dose-dependent manner following transfection of human cells with a hexavalent mRNA mixture encapsulated in lipid nanoparticles (LNPs), despite significant protein sequence homology. Expanding on these efforts, we show the utility of the CFT-MS approach in identifying the presence and junction of +1 ribosomal frameshifting resulting from N1-methylpseudouridation. Overall, this CFT-MS methodology offers a valuable analytical tool for the development and production of mRNA-based vaccines by facilitating the evaluation of mRNA quality and functionality while ensuring accurate translation of antigen proteins.

Abstract Figure
Genetically modifying the protein matrix of macroscopic living materials to control their structure and rheological properties
Authors: Jimenez Esther M. , Nguyen Carlson , Shakeel Ahmad , Tesoriero Robert , Charrier Marimikel , Stull Alanna , Ajo-Franklin Caroline M.
Published: May 2024

The field of engineering living materials (ELMs) seeks to engineer cells to form macroscopic materials with tailorable structures and properties. While centimeter-scale ELMs can be grown fromCaulobacter crescentusengineered to secrete a protein matrix, how the sequence of the protein matrix affects structural and rheological properties remains poorly understood. Here, we explore how changing the elastin-like polypeptide (ELP) length impacts ELM microstructure and viscoelastic behavior. We demonstrate that shortening ELP produces fibers almost 2x thicker than other variants, resulting in a stiffer material at rest. Interestingly, the mid-length ELP forms a complex structure with globules and multidirectional fibers with increased yield stress under flow conditions. Lengthening ELP creates thinner strands between cells with similar storage and loss moduli to the mid-length ELP. This study indicates that sequence-structure-property relationships in these ELMs are complex with few parallels to other biocomposite models. Furthermore, it highlights that fine-tuning genetic sequences can create significant differences in rheological properties, uncovering new design principles of ELMs.
Time of day of infection shapes development of a eukaryotic algal-Nucleocytoviricotavirocell
Authors: Chase Emily E. , Truchon Alexander R. , Creasey Brooke A. , Wilhelm Steven W.
Published: May 2024

Aureococcus anophagefferensrepresents one component of a model host-virus system (with the “giant virus”Kratosvirus quantuckense). Studies to define its ribocell (uninfected cells) and virocell (virus-infected cells) forms are needed, as both are abundant during algal blooms. A linkage between light-derived energy, virus particle production and virocell formation has been noted. We explored how the time of day (morning, afternoon, late day) of virus-host contact shaped virocell ontogeny. In parallel, we explored the need for light derived energy in this mixotrophic plankter by inhibiting photosystem II (PSII). Using flow cytometry and photochemical assessments, we examined the physiology of infected cells and controls, and estimated virus particle production by virocells. We observed distinct differences between ribocell and virocell response to treatments, including reductions in virus particle production during reduced light (i.e.,duration) and PSII inhibition. Collectively this work demonstrates the importance of light in shaping the fate of infected cells and provides insight into the factors that constrainin situblooms. Most significantly, we show that time of day when a virus and host come into contact influences viral particle production, and therefore bloom dynamics; a factor that needs to be considered in future bloom modeling work.
An integrated microfluidic and fluorescence platform for probing in vivo neuropharmacology
Authors: Piantadosi Sean C , Lee Min‐Kyu , Wu Mingzheng , Huynh Huong , Avila Raudel , Pizzano Carina , Zamorano Catalina A , Wu Yixin , Xavier Rachael , Stanslaski Maria , Kang Jiheon , Thai Sarah , Kim Youngdo , Zhang Jinglan , Huang Yonggang , Kozorovitskiy Yevgenia , Good Cameron H , Banks Anthony R , Rogers John A , Bruchas Michael R.
Published: May 2024

Neurotechnologies and genetic tools for dissecting neural circuit functions have advanced rapidly over the past decade, although the development of complementary pharmacological method-ologies has comparatively lagged. Understanding the precise pharmacological mechanisms of neuroactive compounds is critical for advancing basic neurobiology and neuropharmacology, as well as for developing more effective treatments for neurological and neuropsychiatric disorders. However, integrating modern tools for assessing neural activity in large-scale neural networks with spatially localized drug delivery remains a major challenge. Here, we present a dual microfluidic-photometry platform that enables simultaneous intracranial drug delivery with neural dynamics monitoring in the rodent brain. The integrated platform combines a wireless, battery-free, miniaturized fluidic microsystem with optical probes, allowing for spatially and temporally specific drug delivery while recording activity-dependent fluorescence using genetically encoded calcium indicators (GECIs), neurotransmitter sensors GRABNEand GRABDA, and neuropeptide sensors. We demonstrate the performance this platform for investigating neuropharmacological mechanisms in vivo and characterize its efficacy in probing precise mechanistic actions of neuroactive compounds across several rapidly evolving neuroscience domains.
Competition and Integration of Visual and Goal Vector Signals for Spatial Navigation
Authors: Vijayabaskaran Sandhiya , Cheng Sen
Published: May 2024

Abstract

Integrating different sources of information is essential to successful spatial navigation. For instance, animals must often rely on a combination of visual impressions, self-motion, olfaction, and other signals to navigate to a goal. This is especially important when navigating in uncertain environments, where switching from one source of information to another or integrating multiple sources of information may be required to make navigation decisions. We propose a computational model of the interaction of visual and goal-vector signals based on reinforcement learning and use it to study behavior and spatial representations. Our model demonstrates that the ability to navigate using each information source independently, in addition to integrating them, is crucial to successfully navigating in uncertain environments. Counterintuitively, our model also shows that when one of the signals is removed, navigation may be improved if the remaining signal is reliable and sufficient to navigate, however, this improvement comes at the expense of robustness.
Circadian rhythms mediate malaria transmission potential
Authors: Bento Inês , Parrington Brianna , Pascual Rushlenne , Goldberg Alexander S , Wang Eileen , Liu Hani , Zelle Mira , Takahashi Joseph S , Elias Joshua E , Mota Maria M , Rijo-Ferreira Filipa
Published: May 2024

Malaria transmission begins when infected femaleAnophelesmosquitos depositPlasmodiumparasites into the mammalian host’s skin during a bloodmeal. The salivary gland-resident sporozoite parasites migrate to the bloodstream, subsequently invading and replicating within hepatocytes. AsAnophelesmosquitos are more active at night, with a 24-hour rhythm, we investigated whether their salivary glands are under circadian control, anticipating bloodmeals and modulating sporozoite biology for host encounters. Here we show that approximately half of the mosquito salivary gland transcriptome, particularly genes essential for efficient bloodmeals such as anti-blood clotting factors, exhibits circadian rhythmic expression. Furthermore, we demonstrate that mosquitoes prefer to feed during nighttime, with the amount of blood ingested varying cyclically throughout the day. Notably, we show a substantial subset of the sporozoite transcriptome cycling throughout the day. These include genes involved in parasite motility, potentially modulating the ability to initiate infection at different times of day. Thus, although sporozoites are typically considered quiescent, our results demonstrate their transcriptional activity, revealing robust daily rhythms of gene expression. Our findings suggest a circadian evolutionary relationship between the vector, parasite and mammalian host that together modulate malaria transmission.
Amino Acid-Dependent Material Properties of Tetrapeptide Condensates
Authors: Zhang Yi , Prasad Ramesh , Su Siyuan , Lee Daesung , Zhou Huan-Xiang
Published: May 2024

Condensates formed by intrinsically disordered proteins mediate a myriad of cellular processes and are linked to pathological conditions including neurodegeneration. Rules of how different types of amino acids (e.g., π-π pairs) dictate the physical properties of biomolecular condensates are emerging, but our understanding of the roles of different amino acids is far from complete. Here we studied condensates formed by tetrapeptides of the form XXssXX, where X is an amino acid and ss represents a disulfide bond along the backbone. Eight peptides form four types of condensates at different concentrations and pH values: droplets (X = F, L, M, P, V, A); amorphous dense liquids (X = L, M, P, V, A); amorphous aggregates (X = W), and gels (X = I, V, A). The peptides exhibit enormous differences in phase equilibrium and material properties, including a 368-fold range in the threshold concentration for phase separation and a 3856-fold range in viscosity. All-atom molecular dynamics simulations provide physical explanations of these results. The present work also reveals widespread critical behaviors, including critical slowing down manifested by the formation of amorphous dense liquids and critical scaling obeyed by fusion speed, with broad implications for condensate function.
Recognition of RNA secondary structures with a programmable peptide nucleic acid-based platform
Authors: Lu Rongguang , Deng Liping , Lian Yun , Ke Xin , Yang Lixia , Xi Kun , Lerk Ong Alan Ann , Chen Yanyu , Zhou Hanting , Meng Zhenyu , Lin Ruiyu , Fan Shijian , Liu Yining , Toh Desiree-Faye Kaixin , Zhan Xuan , Krishna Manchugondanahalli S. , Patil Kiran M. , Lu Yunpeng , Liu Zheng , Zhu Lizhe , Wang Hongwei , Li Guobao , Chen Gang
Published: May 2024

RNA secondary structures comprise double-stranded (ds) and single-stranded (ss) regions. Antisense peptide nucleic acids (asPNAs) enable the targeting of ssRNAs and weakly formed dsRNAs. Nucleobase-modified dsRNA-binding PNAs (dbPNAs) allow for targeting of relatively stable dsRNAs. A programmable RNA structure-specific targeting strategy is needed for simultaneous recognition of dsRNAs and ssRNAs. Here, we report on combining dbPNAs and asPNAs (designated as daPNAs) for the targeting of dsRNA-ssRNA junctions. Our binding and modeling data suggest that combining traditional asPNA (with a 4-letter code: T, C, A, and G) and dbPNA (with a 4-letter code: T or s2U, L, Q, and E) scaffolds facilitates RNA structure-specific tight binding (nM to μM) under physiologically-relevant conditions. We further applied our daPNAs in substrate specific inhibition of Dicer acting on pre-miR-198 in a cell-free assay and regulating ribosomal frameshifting induced by model hairpins in both cell-free and cell culture assays. daPNAs would be a useful platform for developing chemical probes and therapeutic ligands targeting RNA.

Highlight

We demonstrated that sequence- and structure-specific targeting of RNA can be facilitated by nucleobase-modified dsRNA-binding PNAs (dbPNAs) platform in combination with antisense PNAs (asPNAs). We name the novel PNAs as daPNAs.

daPNAs can be used in a programmable way for targeting RNAs by formation of a short triplex next to a short duplex at a dsRNA-ssRNA junction.

We applied our daPNAs in substrate specific inhibition of Dicer acting on pre-miR-198 in a cell-free assay and regulating ribosomal frameshifting induced by model hairpins in both cell-free and cell culture assays.

The daPNAs platform would serve as useful junction-specific molecular glues for the targeting of many biologically important RNA structures in transcriptomes.
Fluctuations and freezing of biofilm-air interfaces
Authors: Bravo Pablo , Yunker Peter J.
Published: May 2024

The study of interfacial roughening is common in physics, from epitaxial growth in the lab to pio-neering mathematical descriptions of universality in models of growth processes. These studies led to the identification of a series of general principles. Typically, stochastic growth produces an interface that becomes rougher as the deposit grows larger; this roughening can only be counteracted by mechanisms that act on the top of deposit, such as surface tension or surface diffusion. However, even when relaxation mechanisms are present, interfaces that continue to grow stochastically continue to change; new peaks and troughs emerge and disappear as stochastic growth produces a constantly changing, dynamic interface. These universal phenomena have been observed for bacterial colonies in a variety of contexts. However, previous studies have not characterized the interfacial phenomena at the top surface of a colony, i.e., the colony-air interface, when activity is only present at the bottom surface, i.e., the colony-solid interface, where nutrients are available, over long times. As traditional interfacial roughening models primarily focus on activity occurring at the top surface it is unclear what phenomena to expect over long times. Here, we use white light interferometry to study the roughening of bacterial biofilms, from many different species. We find that these colonies are remarkably smooth, suggesting that a mechanism of interfacial relaxation is at play. However, colonies remain remarkably smooth even after growing large. We discover that topographic fluctuations “freeze” in place, despite the fact that growth continues for hundreds of microns more. With simple simulations, we show that this emergent freezing is due to the dampening of fluctuations from cell growth by the cells between the growing zone and the surface. We find that the displacement field caused by a single perturbation decays exponentially, with a decay length ofδL. In line with that observation we also show that the topography ceases to change when perturbations are a distanceδLaway from the surface. Thus, over-damped systems in which activity occurs at the bottom surface represent a distinct class of interfacial growth phenomena, capable of producing frozen topographies and remarkably smooth surfaces from spatially and temporally stochastic growth.
Tuning single-molecule ClyA nanopore tweezers for real-time tracking of the conformational dynamics of West Nile viral NS2B/NS3 protease
Authors: Shorkey Spencer A. , Zhang Yumeng , Sharp Jacqueline , Clingman Sophia , Nguyen Ly , Chen Jianhan , Chen Min
Published: May 2024

The flaviviral NS2B/NS3 protease is a conserved enzyme required for flavivirus replication. Its highly dynamic conformation poses major challenges but also offers opportunities for antiviral inhibition. Here, we established a nanopore tweezers-based platform to monitor NS2B/NS3 conformational dynamics in real-time. Molecular simulations coupled with electrophysiology revealed that the protease could be captured in the middle of the ClyA nanopore lumen, stabilized mainly by dynamic electrostatic interactions. We designed a newSalmonella typhiClyA nanopore with enhanced nanopore/protease interaction that can resolve the open and closed states at the single-molecule level for the first time. We demonstrated that the tailored ClyA could track the conformational transitions of the West Nile NS2B/NS3 protease and unravel the conformational energy landscape of various protease constructs through population and kinetic analysis. The new ClyA-protease platform paves a way to high-throughput screening strategies for discovering new allosteric inhibitors that target the NS2B and NS3 interface.
Deconvolution of polygenic risk score in single cells unravels cellular and molecular heterogeneity of complex human diseases
Authors: Zhang Sai , Shu Hantao , Zhou Jingtian , Rubin-Sigler Jasper , Yang Xiaoyu , Liu Yuxi , Cooper-Knock Johnathan , Monte Emma , Zhu Chenchen , Tu Sharon , Li Han , Tong Mingming , Ecker Joseph , Ichida Justin , Shen Yin , Zeng Jianyang , Tsao Philip , Snyder Michael
Published: May 2024

Polygenic risk scores (PRSs) are commonly used for predicting an individual's genetic risk of complex diseases. Yet, their implication for disease pathogenesis remains largely limited. Here, we introduce scPRS, a geometric deep learning model that constructs single-cell-resolved PRS leveraging reference single-cell chromatin accessibility profiling data to enhance biological discovery as well as disease prediction. Real-world applications across multiple complex diseases, including type 2 diabetes (T2D), hypertrophic cardiomyopathy (HCM), and Alzheimer's disease (AD), showcase the superior prediction power of scPRS compared to traditional PRS methods. Importantly, scPRS not only predicts disease risk but also uncovers disease-relevant cells, such as hormone-high alpha and beta cells for T2D, cardiomyocytes and pericytes for HCM, and astrocytes, microglia and oligodendrocyte progenitor cells for AD. Facilitated by a layered multi-omic analysis, scPRS further identifies cell-type-specific genetic underpinnings, linking disease-associated genetic variants to gene regulation within corresponding cell types. We substantiate the disease relevance of scPRS-prioritized HCM genes and demonstrate that the suppression of these genes in HCM cardiomyocytes is rescued by Mavacamten treatment. Additionally, we establish a novel microglia-specific regulatory relationship between the AD risk variant rs7922621 and its target genesANXA11andTSPAN14. We further illustrate the detrimental effects of suppressing these two genes on microglia phagocytosis. Our work provides a multi-tasking, interpretable framework for precise disease prediction and systematic investigation of the genetic, cellular, and molecular basis of complex diseases, laying the methodological foundation for single-cell genetics.
Cathepsin X is a conserved cell death protein involved in algal response to environmental stress
Authors: Mizrachi Avia , Sadeh Mai , Ben-Dor Shifra , Dym Orly , Ku Chuan , Feldmesser Ester , Zarfin Amichai , Brunson John K. , Allen Andrew E. , Jinkerson Robert E. , Schatz Daniella , Vardi Assaf
Published: May 2024

Phytoplankton play a crucial role in global primary production and can form vast blooms in aquatic ecosystems. Bloom demise and the rapid turnover of phytoplankton are suggested to involve programmed cell death (PCD) induced by diverse environmental stressors. However, fundamental knowledge of the PCD molecular components in algae and protists in general remains elusive. Previously, we revealed that early oxidation in the chloroplast predicted subsequent cell death or survival in isogenic subpopulations that emerged following H2O2treatment in the diatomPhaeodactylum tricornutum. Here, we performed transcriptome analysis of sorted sensitive oxidized cells and resilient reduced cells, to discover genes linked to their contrasting fates. By cross-comparison with a large-scale mutant screen in the green algaChlamydomonas reinhardtii, we identified functionally relevant conserved PCD gene candidates, including the cysteine protease cathepsin X/Z (CPX).CPXmutants inP. tricornutum CPX1andC. reinhardtii CEP12both exhibited profound resilience to oxidative stress, supporting a conserved function in algal PCD.P. tricornutum cpx1mutants, generated using CRISPR-Cas9, also exhibited resilience to the toxic diatom-derived infochemical cyanogen bromide. Phylogenetic and predictive structural analyses show thatCPXis highly conserved in eukaryotes, and algae of the green and red lineages exhibit strong structural similarity to human cathepsinCTSZ.CPXis expressed by diverse algae across the oceans and during toxicPseudo-nitzschiablooms, supporting its ecological importance. Elucidating PCD components in algae sheds light on the evolutionary origin of PCD in unicellular organisms, and on the cellular strategies employed by the population to cope with stressful conditions.
Intracellular Pseudomonas aeruginosa persist and evade antibiotic treatment in a wound infection model
Authors: Pont Stephane , Nilly Flore , Berry Laurence , Bonhoure Anne , Alford Morgan A , Louis Melissande , Nogaret Pauline , Lesouhaitier Olivier , Hancock Robert E.W. , Plesiat Patrick , Blanc-Potard Anne
Published: May 2024

Persistent bacterial infections evade host immunity and resist antibiotic treatments through various mechanisms that are difficult to evaluate in a living host. Pseudomonas aeruginosa is a main cause of chronic infections in patients with cystic fibrosis (CF) and wounds. Here, by immersing wounded zebrafish embryos in a suspension of P. aeruginosa isolates from CF patients, we established a model of persistent infection that mimics a murine chronic skin infection model. Live and electron microscopy revealed persisting aggregated P. aeruginosa inside zebrafish cells, including macrophages, at unprecedented resolution. Persistent P. aeruginosa exhibited adaptive resistance to several antibiotics, host cell permeable drugs being the most efficient. Moreover, persistent bacteria could be partly re-sensitized to antibiotics upon addition of anti-biofilm molecules that dispersed the bacterial aggregates in vivo. Collectively, this study demonstrates that an intracellular location protects P. aeruginosa in vivo from host innate immunity and antibiotics, and provides new insights into efficient treatments against chronic infections.
Calabi-Yau Meets Gravity: A Calabi-Yau Threefold at Fifth Post-Minkowskian Order
Authors: Frellesvig Hjalte , Morales Roger , Wilhelm Matthias
Published: May 2024

We study geometries occurring in Feynman integrals that contribute to the scattering of black holes in the post-Minkowskian (PM) expansion. These geometries become relevant to gravitational-wave production from binary mergers through the classical conservative potential. At 4PM, a K3 surface is known to occur in a three-loop integral, leading to elliptic integrals in the result. In this Letter, we identify a Calabi-Yau threefold in a four-loop integral, contributing at 5PM. The presence of this Calabi-Yau geometry indicates that completely new functions occur in the full analytical results.

Published by the American Physical Society
2024
Parameter-setting heuristic for the quantum alternating operator ansatz
Authors: Sud James , Hadfield Stuart , Rieffel Eleanor , Tubman Norm , Hogg Tad
Published: May 2024

The quantum alternating operator ansatz (QAOA) is a generalized approach for solving challenging optimization problems that builds on the alternating structure of the quantum approximate optimization algorithm. Finding high-quality parameters efficiently for QAOA remains a major challenge in practice. In this work, we introduce a classical strategy for parameter setting, suitable for cases in which the number of distinct cost values grows only polynomially with the problem size, such as is common for constraint-satisfaction problems. The crux of our strategy is that we replace the cost function expectation value step of QAOA with a classical model that can be efficiently evaluated classically and has parameters which play an analogous role to the QAOA parameters. This model is based on empirical observations that, in some QAOA states, variable configurations with the same cost have the same amplitudes from step to step. We define this class of states as homogeneous states. For problems with particular symmetries, QAOA states are guaranteed to be homogeneous. More generally, high overlaps between QAOA states and homogeneous states have been empirically observed in a number of settings. Building on this idea, we define a classical homogeneous proxy for QAOA in which this property holds exactly and which yields information describing both states and expectation values. We then classically determine high-quality parameters for this proxy and then use these parameters in QAOA, an approach we label the homogeneous heuristic for parameter setting. We numerically examine this heuristic for MaxCut on unweighted Erdős-Rényi random graphs. For up to three QAOA levels we demonstrate that the heuristic is easily able to find parameters that match approximation ratios corresponding to previously found globally optimized approaches. For levels up to 20 we obtain parameters using our heuristic with approximation ratios monotonically increasing with depth, while a strategy that uses parameter transfer instead fails to converge with comparable classical resources. These results suggest that our heuristic may find good parameters in regimes that are intractable with noisy intermediate-scale quantum devices. Finally, we outline how our heuristic may be applied to wider classes of problems.

Published by the American Physical Society
2024
Corporate governance and corporate sustainability performance: the mediating role of CSR expenditure
Authors: Rashid Md Mamunur , Kabir Md Rabiul
Published: May 2024

Purpose

This study investigates the effect of corporate governance (CG) characteristics on corporate sustainability performance (CSP) and whether the magnitude of CSR expenditure mediates such a relationship in the context of an emerging and developing economy-Bangladesh.

Design/methodology/approach

This study collects data from the annual reports of 30 private commercial banks listed with the Dhaka Stock Exchange for the period starting from 2013 to 2022, giving 300 firm-year observations. To test the hypotheses formulated, this study uses Baron and Kenny’s (1986) four-step model. Data have been analyzed using AMOS 23 to examine the direct and indirect effect of CG on sustainability performance.

Findings

This study finds that several CG variables (board size, board independence, sustainable finance committee) significantly affect several facets of sustainability performance (environmental, social, and financial performance). However, the mediating role of the magnitude of CSR expenditure in the relationship between CG mechanisms and sustainability performance is found to be limited.

Research limitations/implications

The list of CG and ownership structure variables studied is not exhaustive, and the presence of a wide variation in the measurement of sustainability performance makes its measurement subjective to some extent.

Originality/value

This study uses the magnitude of CSR expenditure as a mediator in the relationship between CG and sustainability performance, which is rarely addressed by the extant literature in this field.
Seeding innovation: the role of internal and external digital data in agri-food product innovation
Authors: Frau Moreno , Keszey Tamara
Published: May 2024

Purpose

Since previous literature provides fragmented and conflicting results about the use of digital data for product innovation, the article aims to comprehensively explore and shed light on how agri-food firms utilise external and internal digital data sources when dealing with different product innovations, such as incremental, architecture and radical innovation.

Design/methodology/approach

This paper adopts an exploratory multiple-case study and a theory-building process, focussing on the agri-food industry. We collected primary and secondary data from eight manufacturing companies.

Findings

The findings of this research show an empirical framework of six agri-food firms’ digital data utilisation behaviours: the supervisor, the passive supervisor, the developer, the passive developer, the pathfinder and the conjunction behaviour. These digital data utilisation behaviours vary according to a combination of data sources, such as internal data related to inside phenomenon measures (e.g. data generated by sensors installed in the production plan) or external data (e.g., market trends, overall sector sales), and innovation purposes.

Practical implications

This article offers guiding principles that assist agri-food companies when utilising internal and external digital data sources for specific product innovation outcomes such as incremental, architectural and radical innovation.

Originality/value

The significance of external and internal data sources in stimulating product innovation has garnered substantial attention within academic discussions, highlighting the critical importance of analysing digital data for driving such innovation. Nonetheless, the predominant approach is to study a single innovation outcome through the lens of digital technology. In contrast, our study stands out by adopting a fundamental perspective on data sources, enabling a more nuanced explanation of the overall product innovation outcomes within the agri-food sector.
Driving metaverse adoption in the hospitality industry: an upper echelon perspective
Authors: Agnihotri Arpita , Bhattacharya Saurabh , Sakka Georgia , Vrontis Demetris
Published: May 2024

Purpose

The purpose of this study is to explore how past and future temporal focus of CEOs in the hospitality industry influence their intention to invest in metaverse technology and the underlying mechanism under boundary conditions of perceived competitive pressure.

Design/methodology/approach

This multi-informant study collected data over three waves from a sample of 235 CEOs and their subordinates in India’s hospitality industry. A PLS-SEM was applied to the study data. Further, the study also used phenomenological interviews to capture CEOs’ perspectives on the study’s conceptual model.

Findings

Findings suggest that the past temporal focus of CEOs decreases technology orientation, and future temporal focus increases the technology orientation of firms, consequently impacting the intention to invest in the metaverse. CEOs’ perceived competitive pressure moderates the mediating relationship, such that the negative impact of past temporal focus on technology orientation is decreased and that of future temporal focus on the CEO is increased.

Research limitations/implications

By exploring the role of a CEO’s past and future temporal focus on influencing technology orientation and, hence, adoption of new technology, the study extends upper-echelon theory to the field of metaverse adoption in the hospitality industry and responds to scholars’ calls to explore the industry’s technology adoption from the lens of the upper echelon.

Practical implications

The study has significant implications for the success of the adoption of metaverse technology in the hospitality industry. Findings imply that the board members should encourage CEOs to have future temporal focus.

Originality/value

The study provides novel insights into the adoption of metaverse technology by the hospitality industry, where CEO attributes such as their temporal focus influence intention to invest in metaverse.
Motivating supervisors during disability accommodation: a comprehensive examination on job demand and resources theories
Authors: Alam Mohammad Shahin , Williams-Whitt Kelly , Shin DuckJung , Ansari Mahfooz
Published: May 2024

Purpose

This study develops and tests a comprehensive model that examines whether dimensions of supervisors’ job demands and resources influence their work motivation through their job strain levels while managing disability accommodation (DA).

Design/methodology/approach

The proposed model leverages the assumptions of established job demand and resources theories, including demand-ability fit, job demand-control, job demand-control-support, and effort-reward balance models. Then, we tested with the quantitative data from 335 British, Canadian, American, Australian, Dutch, and German supervisors with recent DA experience.

Findings

This study found support for the proposed model. Job control and social support directly affected work motivation, while job strain did not mediate the relationship between job control and social support and work motivation. The results suggest that employers looking to improve the likelihood of DA success should focus on providing adequate job control, social support, and rewards to supervisors responsible for accommodating employees with disabilities.

Practical implications

This research enhances our understanding of how additional DA responsibilities impact supervisors and aids in the development of effective DA management policies and interventions, providing robust support for practitioners.

Originality/value

This study contributes to extending the DA literature by testing the applicability of different theoretical models to explain the effect of the additional DA responsibility on supervisors’ job demand, strain, and motivation levels and identify the resources to mitigate them.
When friends are near foes: governing nonequity alliances with steering committees
Authors: Tseng Chiung-Hui , Lien Nguyen Thi Kim
Published: May 2024

Purpose

Indirect knowledge leakage to rivals located near alliance partners represents a significant risk that has received limited scholarly attention. Hence, the question of how to manage this risk – which the authors term “partner-rival co-location risk” – in nonequity alliances remains unanswered, and this study aims to suggest establishing a steering committee to oversee the partnership.

Design/methodology/approach

Drawing on the agglomeration economies and alliance governance literatures, the authors develop a set of hypotheses and perform a series of empirical tests on 470 nonequity alliances in the US biopharmaceutical industry.

Findings

The authors propose that there is a positive linkage between partner-rival co-location risk and the formation of a steering committee in a nonequity alliance, which receives strong empirical support. Further, this relationship is significantly moderated by the breadth (alliance scope) but not the depth (reciprocal interdependence) of interaction between the partnering firms.

Originality/value

This paper is a pioneer to shed light on “partner-rival co-location risk” and how partner-rival co-location risk affects the governance decision of whether to establish a steering committee in a nonequity alliance, thus offering important theoretical and practical insights into competition and cooperation in alliance management.
Visualising knowledge: a survey of infographic perceptions and challenges in academic library settings
Authors: Butdisuwan Sujin , Kataria Sanjay , Taj Amreen , Subaveerapandiyan A.
Published: May 2024

Purpose

This study investigates the perceptions and challenges faced by academic library professionals in utilising infographics as a communication tool. It aims to understand how infographics are perceived in libraries, their effectiveness in conveying information and the obstacles encountered during implementation.

Design/methodology/approach

The research employed a descriptive survey design, collecting data through a closed-ended questionnaire distributed electronically to 144 library and information science professionals. Stratified random sampling was used to ensure representation from various types of libraries. Pilot testing was conducted to validate the questionnaire, and data analysis was performed using statistical software.

Findings

Library professionals perceive infographics as valuable tools for conveying complex concepts quickly, promoting library events and appealingly presenting resources. They also believe that infographics simplify complex information and enhance the user experience. However, challenges include lacking design skills and resources, difficulty finding relevant data, integrating infographics into traditional library services and time constraints.

Originality/value

This study provides unique insights into the role of infographics in library communication, highlighting both their positive perceptions and critical challenges. It offers recommendations for enhancing the use of infographics, including training for library professionals, improved data management and integration into traditional library services. The study also suggests promoting best practices and exploring emerging technologies like 3D interactive infographics.