bluuebunny/crossref_metadata_2025 huggingface dataset:
IGF-1 Peptide Mimetic-functionalized Hydrogels Enhance MSC Survival and Immunomodulatory Activity
Authors: Tan Xiaohong , Jing Liufang , Neal Sydney M. , Gupta Munish C. , Buchowski Jacob M. , Setton Lori A. , Huebsch Nathaniel
Published: July 2024

Human mesenchymal stem cells (MSCs) have demonstrated promise when delivered to damaged tissue or tissue defects for their cytokine secretion and inflammation modulation behaviors that can promote repair. Insulin-like growth factor 1 (IGF-1) has been shown to augment MSCs’ viability and survival and promote their secretion of cytokines that signal to endogenous cells, in the treatment of myocardial infarction, wound healing, and age-related diseases. Biomaterial cell carriers can be functionalized with growth factor-mimetic peptides to enhance MSC function while promoting cell retention and minimizing off-target effects seen with direct administration of soluble growth factors. Here, we functionalized alginate hydrogels with three distinct IGF-1 peptide mimetics and the integrin-binding peptide, cyclic RGD. One IGF-1 peptide mimetic (IGM-3) was found to activate Akt signaling and support survival of serum-deprived MSCs. MSCs encapsulated in alginate hydrogels that presented both IGM-3 and cRGD showed a significant reduction in pro-inflammatory cytokine secretion when challenged with interleukin-1β. Finally, MSCs cultured within the cRGD/IGM-3 hydrogels were able to blunt pro-inflammatory gene expression of human primary cells from degenerated intervertebral discs. These studies indicate the potential to leverage cell adhesive and IGF-1 growth factor peptide mimetics together to control therapeutic secretory behavior of MSCs.

Significance Statement

Insulin-like growth factor 1 (IGF-1) plays a multifaceted role in stem cell biology and may promote proliferation, survival, migration, and immunomodulation for MSCs. In this study, we functionalized alginate hydrogels with integrin-binding and IGF-1 peptide mimetics to investigate their impact on MSC function. Embedding MSCs in these hydrogels enhanced their ability to reduce inflammatory cytokine production and promote anti-inflammatory gene expression in cells from degenerative human intervertebral discs exposed to proteins secreted by the MSC. This approach suggests a new way to retain and augment MSC functionality using IGF-1 peptide mimetics, offering an alternative to co-delivery of cells and high dose soluble growth factors for tissue repair and immune- system modulation.
Lineage-dependence of the neuroblastoma surfaceome defines tumor cell state-dependent and independent immunotherapeutic targets
Authors: Kendsersky Nathan M. , Odrobina Michal , Mabe Nathaniel W. , Farrel Alvin , Grossmann Liron , Tsang Matthew , Groff David , Wolpaw Adam J. , Zammarchi Francesca , van Berkel Patrick H. , Dang Chi V. , Mossé Yaël P. , Stegmaier Kimberly , Maris John M.
Published: July 2024

Background

Neuroblastoma is a heterogeneous disease with adrenergic (ADRN)- and therapy resistant mesenchymal (MES)-like cells driven by distinct transcription factor networks. Here, we investigate the expression of immunotherapeutic targets in each neuroblastoma subtype and propose pan-neuroblastoma and cell state specific targetable cell-surface proteins.

Methods

We characterized cell lines, patient-derived xenografts, and patient samples as ADRN-dominant or MES- dominant to define subtype-specific and pan-neuroblastoma gene sets. Targets were validated with ChIP- sequencing, immunoblotting, and flow cytometry in neuroblastoma cell lines and isogenic ADRN-to-MES transition cell line models. Finally, we evaluated the activity of MES-specific agentsin vivoandin vitro.

Results

Most immunotherapeutic targets being developed for neuroblastoma showed significantly higher expression in the ADRN subtype with limited expression in MES-like tumor cells. In contrast,CD276(B7-H3) andL1CAMmaintained expression across both ADRN and MES states. We identified several receptor tyrosine kinases (RTKs) enriched in MES-dominant samples and showed that AXL targeting with ADCT-601 was potently cytotoxic in MES-dominant cell lines and showed specific anti-tumor activity in a MES cell line-derived xenograft.

Conclusions

Immunotherapeutic strategies for neuroblastoma must address the potential of epigenetic downregulation of antigen density as a mechanism for immune evasion. We identified several RTKs as candidate MES-specific immunotherapeutic target proteins for the elimination of therapy-resistant cells. We hypothesize that the phenomena of immune escape will be less likely when targeting pan-neuroblastoma cell surface proteins such as B7-H3 and L1CAM, and/or dual targeting strategies that consider both the ADRN- and MES-cell states.

Key Points

Cellular plasticity influences the abundance of immunotherapeutic targets.

Subtype-specific targets may be susceptible to epigenetically-mediated downregulation.

Immunotherapeutic targets in development, B7-H3 and L1CAM, show “pan-subtype” expression.

Importance of Study

Neuroblastoma is a lethal childhood malignancy that shows cellular plasticity in response to anti-cancer therapies. Several plasma membrane proteins are being developed as immunotherapeutic targets in this disease. Here we define which cell surface proteins are susceptible to epigenetically regulated downregulation during an adrenergic to mesenchymal cell state switch and propose immunotherapeutic strategies to anticipate and circumvent acquired immunotherapeutic resistance.
A comparative analysis across species of maternal mRNA regulation in embryos using QUANTA
Authors: Tawil Mazal , Alcalay Dina , Greenberg Pnina , Har-Sheffer Shirel , Fishman Lior , Rabani Michal
Published: July 2024

Abstract

The post-transcriptional regulation of mRNAs greatly impacts gene expression dynamics, but the underlying regulatory kinetics and sequence rules and how they change between organisms remain elusive. Thousands of pre-loaded maternal transcripts are post-transcriptionally regulated within metazoan embryos, making it an ideal system to investigate mRNA regulation. We present QUANTA, a computational strategy to distinguish transcriptionally silent genes and analyze their regulation. QUANTA uses kinetic models to compare total and polyA+ expression patterns, and dissect quantitative rates of mRNA polyadenylation and degradation. QUANTA analysis of maternally provided mRNAs in zebrafish, frog, mouse and human embryos shows that widespread polyadenylation precedes their degradation. Degradation rates are proportional to the developmental pace of organisms and diverge between orthologs. Rates also scale by adjusting developmental pace of zebrafish with external temperature. Finally, we implement a massively parallel reporter assay that is compatible with QUANTA analysis in zebrafish embryos, and analyze the effects of 3’UTR sequences on mRNA kinetics. We pinpoint potential regulatory signals in 3’UTRs of each organism. These reveal signals to accelerate maternal degradation in fast-developing organisms, while in slow-developing organisms signals enhance mRNA stability. Our work provides a general strategy to quantify post-transcriptional mRNA kinetics and investigate its sequence-based rules.
Glycation of alpha-synuclein enhances aggregation and neuroinflammatory responses
Authors: Vasili Eftychia , König Annekatrin , Al-Azzani Mohammed , Bosbach Clara , Gatzemeier Luisa Maria , Chegão Ana , Miranda Hugo Vicente , Erskine Daniel , Outeiro Tiago F.
Published: July 2024

The risk of developing Parkinson’s disease (PD) is elevated in people with type 2 diabetes, but the precise molecular pathways underlying this connection are still unclear. One hypothesis is that glycation, a non-enzymatic family of reactions between glycating agents, such as reducing sugars or reactive dicarbonyls, and specific amino acids, such as lysines and arginines, may alter proteostasis and trigger pathological alterations. Glycation of alpha-synuclein (aSyn), a central player in PD pathology, causes profound changes in the aggregation process of aSyn. Methylglyoxal (MGO), a strong glycating agent, induces the formation of pathological inclusions enriched in phosphorylated aSyn on serine 129 (pS129). In addition, we found that neuroinflammatory responses are enhanced by MGO-mediated aSyn glycation. Using novel polyclonal antibodies developed towards specific MGO-glycated aSyn residues, we confirmed the occurrence of glycated aSyn bothin vitroas well as in animal and in human brain tissue. In total, our findings shed light into the interplay between glycation, PD, and type 2 diabetes, potentially paving the way for the development of novel therapeutic strategies targeting these intertwined conditions.
TCRfinder: Improved TCR virtual screening for novel antigenic peptides with tailored language models
Authors: Li Yang , Zhang Chaoting , Zhang Xi , Zhang Yang
Published: July 2024

Accurate modeling of T-cell receptor (TCR) and peptide interactions is essential for immunoreaction elucidation and T-cell-based immunotherapeutic developments. We developed TCRfinder, a novel deep-learning architecture for TCR-peptide binding prediction and virtual screening. Large-scale benchmark experiments demonstrated a robust capability of TCRfinder in distinguishing interacting and non-interacting TCRs for unseen peptides, with accuracy significantly beyond current state-of-the-art methods. Furthermore, TCRfinder recognizes tumor neoantigen mutations from wild-type antigens of given TCRs, with a success rate nearly 50% higher than the best of existing methods. Detailed data analyses showed that the major advantage of TCRfinder lies in the specially trained TCR and peptide language models tailored with iterative attention network architecture, which can precisely reveal physical interaction patterns of cross-chain atoms and substantially enhance the precision of TCR-peptide interaction predictions. The open-source TCRfinder program can help facilitate large-scale deployment of high-quality TCR and neoantigen virtual screening, offering exciting potential for personalized TCR-based immunotherapies.
circPCMTD1: A protein-coding circular RNA that regulates DNA damage response inBCR/ABL-positive leukemias
Authors: Papaioannou Dimitrios , Urs Amog P. , Buisson Rémi , Petri Andreas , Kulkarni Rohan , Nicolet Deedra , Woodward Lauren , Goda Chinmayee , Mrózek Krzysztof , Behbehani Gregory K. , Kauppinen Sakari , Eisfeld Ann-Kathrin , Aifantis Iannis , Singh Guramrit , Dorrance Adrienne M. , Garzon Ramiro
Published: July 2024

Circular RNAs are a novel class of RNA transcripts, which regulate important cellular functions in health and disease. Herein, we report on the functional relevance of thecircPCMTD1transcript in acute leukemias. In screening experiments, we found thatcircPCMTD1depletion strongly inhibited the proliferative capacity of leukemic cells withBCR-ABLtranslocations. Mass cytometry experiments identified the aberrant activation of the DNA damage response as an early downstream event ofcircPCMTD1depletion. Inin vivoexperiments,circPCMTD1targeting prolonged the survival of mice engrafted with leukemic blasts harboring the Philadelphia chromosome. Mechanistically, we found thatcircPCMTD1was enriched in the cytoplasm and associated with the ribosomes of the leukemic cells. We detected a cryptic open reading frame within thecircPCMTD1sequence and found thatcircPCMTD1could generate a peptide product. ThecircPCMTD1-derived peptide interacted with proteins of the BTR complex and enhanced BTR complex formation, thereby increasing tolerance to genotoxic stress.
spatialGE: A user-friendly web application to democratize spatial transcriptomics analysis
Authors: Ospina Oscar E. , Manjarres-Betancur Roberto , Gonzalez-Calderon Guillermo , Soupir Alex C. , Smalley Inna , Tsai Kenneth , Markowitz Joseph , Vallebuona Ethan , Berglund Anders , Eschrich Steven , Yu Xiaoqing , Fridley Brooke L.
Published: July 2024

Spatial transcriptomics (ST) is a powerful tool for understanding tissue biology and disease mechanisms. However, its potential is often underutilized due to the advanced data analysis and programming skills required. To address this, we present spatialGE, a web application that simplifies the analysis of ST data. The application spatialGE provides a user-friendly interface that guides users without programming expertise through various analysis pipelines, including quality control, normalization, domain detection, phenotyping, and multiple spatial analyses. It also enables comparative analysis among samples and supports various ST technologies. We demonstrate the utility of spatialGE through its application in studying the tumor microenvironment of melanoma brain metastasis and Merkel cell carcinoma. Our results highlight the ability of spatialGE to identify spatial gene expression patterns and enrichments, providing valuable insights into the tumor microenvironment and its utility in democratizing ST data analysis for the wider scientific community.
Reward integration in prefrontal-cortical and ventral-hippocampal nucleus accumbens inputs cooperatively modulates engagement
Authors: Iyer Eshaan S. , Vitaro Peter , Wu Serena , Muir Jessie , Tse Yiu Chung , Cvetkovska Vedrana , Bagot Rosemary C.
Published: July 2024

The NAc, a highly integrative brain region controlling motivated behavior, is thought to receive distinct information from various glutamatergic inputs yet strong evidence of functional specialization of inputs is lacking. While circuit neuroscience commonly seeks specific functions for specific circuits, redundancy can be highly adaptive and is a critical motif in circuit organization. Using dual-site fiber photometry in an operant reward task, we simultaneously recorded from two NAc glutamatergic afferents to assess circuit specialization. We identify a common neural motif that integrates reward history in medial prefrontal cortex (mPFC) and ventral hippocampus (vHip) inputs to NAc. Then, by systematically degrading task complexity, dissociating reward from choice and action, we identify key circuit-specificity in the behavioral conditions that recruit encoding. While mPFC-NAc invariantly encodes reward, vHip-NAc encoding is uniquely anchored to loss. Ultimately, using optogenetic stimulation we demonstrate that both inputs co-operatively modulate task engagement. We illustrate how similar encoding, with differential gating by behavioral state, supports state-sensitive tuning of reward-motivated behavior.
Inexperienced bumble bees are poor at securely landing regardless of flower orientation or presence of labellum
Authors: McWaters S.R. , Popp S. , Rivera M. D. , Mendoza F. , Dornhaus A.
Published: July 2024

The mutualism between bees and flowers creates strong selection on both the structure of the flower and behavior of the bee to maximize pollination and foraging success, respectively. Previous research has primarily assessed the costs of foraging by quantifying the time and accuracy of search, and handling time of the flower. However, there is little attention given to the actual success of landing, and it is often not explicitly stated whether failed landing attempts are taken into consideration. We show here that landing attempts often are unsuccessful, especially in inexperienced bees. Orientation of artificial flowers in our experiment neither influenced the preference nor landing success of a naive bumble bee forager. The presence of a labellum, often considered to serve as a landing platform, also did not influence landing success, indicating that it may mostly play a role in flower recognition or act as a nectar guide. Failed landing attempts may thus play an under-recognized role in the foraging efficiency and behavior of bees, and learning may be key in individual bee landing efficiency, not just flower recognition. Further research should aim to quantify the costs of landing failures and consider the role of experience in individual bee landing success.
Mortality, morbidity, and post-operative complications of typhoid intestinal perforations: global systematic review and meta-analysis
Authors: Hagedoorn Nienke N. , Birkhold Megan , Murthy Shruti , Rathan Meera D. , Marchello Christian S. , Crump John A.
Published: July 2024

STRUCTURED ABSTRACT

Objective

We aimed to review global studies reporting on mortality, morbidity, and post-operative complications in patients with typhoid intestinal perforation (TIP).

Summary Background Data

TIP is a serious and life-threatening complication of typhoid fever that requires emergency surgery and an important driver of typhoid burden.

Methods

We searched multiple databases for articles reporting case-fatality ratio (CFR) or complications in patients with TIP undergoing surgery published from 1980 through 30 January 2024. We described the prevalence of each reported complication. Of patients with TIP, we pooled CFR using random-effects meta-analysis and stratified by United Nations region, sex, and number of perforations per patient.

Results

We included 46 articles reporting on 4,317 patients with TIP. The most prevalent post-operative complications were wound or surgical site infection in 1,537 (50.7%) of 3,030 patients, wound dehiscence in 308 (16.1%) of 1,909, and chest infection in 136 (15.6%) of 872. Overall, the pooled CFR (95%CI) of patients with TIP was 15.6% (12.5-18.9%), and was 20.5% (17.1-23.9%) in 30 observations from the African region, 5.7% (2.6-9.6%) in 15 observations from the Asian region, and 12.2% (0.90-30.4%) in three observations from the Americas. The Pearson’s correlation coefficient of median year of data collection and CFR was -0.01 (p=0.95) for Africa and -0.69 (p <0.01) for Asia.

Conclusions

Disability and death associated with TIP remains substantial. Efforts to reduce the occurrence of TIP through typhoid prevention with vaccine and non-vaccine measures, and increased access to and quality of surgical services for those with TIP are warranted.
Phospholipase Cγ regulates lacrimal gland branching by competing with PI3K in phosphoinositide metabolism
Authors: Wang Qian , Tao Chenqi , Wu Yihua , Anderson Karen E. , Hannan Abdul , Lin Chyuan-sheng , Hawkins Phillip , Stephens Len , Zhang Xin
Published: July 2024

Although the regulation of branching morphogenesis by spatially distributed cues is well established, the role of intracellular signaling in determining the branching pattern remains poorly understood. In this study, we investigated the regulation and function of phospholipase C gamma (PLCγ) in Fibroblast Growth Factor (FGF) signaling in lacrimal gland development. We showed that deletion ofPLCγ1in the lacrimal gland epithelium leads to ectopic branching and acinar hyperplasia, which was phenocopied by either mutating the PLCγ1 binding site on Fgfr2 or disabling any of its SH2 domains.PLCγ1inactivation did not change the level of Fgfr2 or affect MAPK signaling, but instead led to sustained AKT phosphorylation due to increased PIP3 production. Consistent with this,PLCγ1mutant phenotype can be reproduced by elevation of PI3K signaling inPtenknockout and attenuated by blocking AKT signaling. This study demonstrated that PLCγ modulates PI3K signaling by shifting phosphoinositide metabolism, revealing an important role of signaling dynamics in conjunction with spatial cues in shaping branching morphogenesis.
An Atlas of Protein Phosphorylation Dynamics During Interferon Signaling
Authors: Busnadiego Idoia , Lork Marie , Fernbach Sonja , Schiefer Samira , Tsolakos Nikos , Hale Benjamin G.
Published: July 2024

Interferons (IFNs, types I-III) have pleiotropic functions in promoting antiviral and anti-tumor responses, as well as in modulating inflammation. Dissecting the signaling mechanisms elicited by different IFNs is therefore critical to understand their phenotypes. Here, we use mass spectrometry to investigate the early temporal dynamics of cellular protein phosphorylation in response to stimulation with IFNα2, IFNβ, IFNω, IFNγ, and IFNλ1, representing all IFN types. We report an atlas of over 700 common or unique phosphorylation events reprogrammed by these IFNs, revealing both previously known and uncharacterized modifications. Functional screening and mechanistic studies identify that several factors differentially-modified in response to IFNs contribute to host antiviral responses, either directly or by supporting IFN-stimulated gene or protein production. Among these, phosphorylation of PLEKHG3 at serine-1081 creates a phospho-regulated binding motif for the docking of 14-3-3 proteins, and together these factors contribute to coordinating efficient IFN-stimulated gene expression independent of early JAK/STAT signaling. Our findings map the global phosphorylation landscapes regulated by IFN types I, II, and III, and provide a key resource to explore their functional consequences.
Glial voltage-gated K+channels modulate the neural abiotic stress tolerance ofDrosophila melanogaster
Authors: Andersen Mads Kuhlmann , Livingston Dawson B. H. , Robertson R. Meldrum , MacMillan Heath A.
Published: July 2024

Severe abiotic stress causes insects to lose nervous function and enter a state of paralytic coma. Central to this loss of function is a spreading depolarization (SD), where a characteristic collapse of ion gradients depolarizes neuronal and glial membranes and rapidly shuts down the CNS. Despite representing a critical limit to CNS function, the stress threshold that elicits SD can be altered by the process of acclimation, though the mechanisms underlying this response remain largely unknown. Here, we made electrophysiological measurements of SD and investigated the role of K+channels in acclimation of the CNS stress response ofDrosophila melanogaster. First, we demonstrate that improved cold tolerance in the CNS elicited by cold acclimation was abolished by pharmacological blockade of K+channels with voltage-gated K+channels representing most of this effect. Next, we used the UAS/Gal4 model system to screen for candidate genes encoding glial voltage-gated K+channels and found that knockdown ofsei- andShaw-encoded channels mimicked the effect of K+blockade in cold-acclimated flies. Furthermore we show that the knockdown of glialsei-encoded channels also impair tolerance to anoxia and heat stress. These findings suggest that voltage-gated K+channels, especially those encoded bysei, are integral to the CNS stress- and acclimation-response and we posit that this is elicited through mechanisms involving glial spatial buffering and barrier function. Establishing such causal links between tissue-specific expression of candidate genes and SD mechanisms will inevitably aid our understanding of insect ecophysiology and SD-related neuropathologies.

New and Noteworthy

Using thermal acclimation and pharmacology, we demonstrate that voltage-gated K+channels are involved in setting the threshold for cold-induced spreading depolarization (SD) in theDrosophila melanogasterCNS. Glial knockdown of channels encoded byseiandShawreduced the resistance to cold-induced SD, highlighting their importance in acclimation of the CNS. Glia-specificsei-knockdown also reduced tolerance to anoxia and heat. We posit thatsei-channels are involved the CNS stress- and acclimation-responses through glial spatial buffering mechanisms.
Dynamic regions allosterically connect the USP14 active site with the proteasome interaction surface
Authors: Salomonsson Johannes , Sjöstrand Linda , Eskilson Arvid , Derbyshire Dean , D’Arcy Pádraig , Sunnerhagen Maria , Ahlner Alexandra
Published: July 2024

Ubiquitin-specificprotease 14 (USP14), is a member of the USP family responsible for the catalytic removal of ubiquitin (Ub) from proteins directed to the proteasome, implicated in the pathogenesis of neurodegeneration and cancer. Crystallography and cryo-EM analysis have identified loop regions crucial for the deubiquitinase activity of USP14, specifically those involved in Ub and proteasome binding. However, the structural changes in USP14 upon ligand binding to these regions are minimal, indicating significant yet uncharacterized dynamic contributions to its function. In this study, through structural and dynamical NMR experiments and functional evaluation, we demonstrate that small mutations designed to impact Ub binding and catalytic activity without disturbing the USP structure display both local and long-range effects. The affected residues connect the active site and the Ub binding region with the proteasome interaction surface through a network of loops, which show varied dynamics on the ps-ms time scale. Collectively, our findings experimentally reveal different aspects of dynamic connections within USP14, suggesting the presence of allosteric networks that link enzyme activity with regulatory function. The novel concept that USP14 allosteric networks are pre-existing, coupled, and activated by regulatory interactions with the USP fold, could be crucial to future targeted drug design.
Berberine Bridge enzyme-like oxidases orchestrate homeostatic control and signaling of oligogalacturonides in defense and wounding
Authors: Salvati Ascenzo , Diomaiuti Alessandra , Locci Federica , Gravino Matteo , Gramegna Giovanna , Ilyas Muhammad , Benedetti Manuel , Costantini Sara , De Caroli Monica , Castel Baptiste , Jones Jonathan D. G. , Cervone Felice , Pontiggia Daniela , De Lorenzo Giulia
Published: July 2024

Plant immunity is triggered by endogenous elicitors known as damage-associated molecular patterns (DAMPs). Oligogalacturonides (OGs) are DAMPs released from the cell wall (CW) demethylated homogalacturonan during microbial colonization, mechanical or pest-provoked tissue damage, and physiological CW remodeling. Berberine Bridge Enzyme-like (BBE-l) proteins named OG oxidases (OGOXs) have been proposed to govern OGs homeostasis, which is necessary to avoid deleterious growth-affecting hyper-immunity and possible cell death. Using OGOX1 over-expressing lines andogox1/2double mutants, we show that these enzymes determine the levels of active OGs vs. inactive oxidized products (oxOGs). Theogox1/2-deficient plants have elevated levels of OGs, while plants overexpressing OGOX1 accumulate oxOGs. The balance between OGs and oxOGs affect disease resistance againstPseudomonas syringae pv tomato,Pectobacterium carotovorum,andBotrytis cinereadepending on the microbial capacity to respond to OGs and metabolize oxOGs. Gene expression upon plant infiltration with OGs reveals that OGOXs orchestrate OG signaling in defense as well as upon tissue damage, pointing to these enzymes as apoplastic players in immunity and tissue repair.

Teaser

Oxidases control the homeostasis of oligogalacturonides in the cell wall and play a pivotal role in the plant immunity.
Iron deprivation activates aboveground cell wall biosynthesis inPopulusand the role of PtrbHLH011
Authors: Tadesse Dimiru , Dai Yuqiu , Yang Lin , Yang Yang , Dwivedi Nidhi , Kumaran Desigan , Blaby-Haas Crysten E. , Lipzen Anna , Santiago Kassandra , Barry Kerrie , Liu Chang-Jun , Xie Meng
Published: July 2024

Lack of mechanistic understanding of the environmental plasticity of secondary cell wall (SCW) biosynthesis hinders the massive bioenergy production on marginal lands. Growing bioenergy crops on marginal lands is appealing to minimize competition for arable land. However, abiotic stresses, particularly iron deficiency stress, are widespread to perturb SCW biosynthesis. In poplar, a major bioenergy crop, we demonstrated that iron deprivation activates stem SCW biosynthesis and identified transcription factor PtrbHLH011 as a possible underlying regulator. PtrbHLH011 is a potent repressor of SCW, whose overexpression resulted in a reduction of stem SCW by over 65%. Our genomic and molecular studies discovered that PtrbHLH011 binds to the AAAGACA sequence and represses essential genes for SCW biosynthesis, flavonoid biosynthesis, and iron homeostasis. Wood formation and iron deprivation downregulates PtrbHLH011 to release the transcriptional repression. Our findings reveal a regulatory mechanism coordinating SCW biosynthesis in response to environmental iron availability and suggest that PtrbHLH011 manipulation may help engineer bioenergy crops with improved performance under marginal conditions.
Maloja: simple and scalable Snakemake workflow orchestration in the cloud
Authors: Giustizia Joseph , Hodgson Wilson , Andress Cameron , Bilkhu Satpal , Macklin James A , Kess Tony
Published: July 2024

As sequencing technologies have matured, bioinformatics tasks have become more complex, computationally demanding, and data intensive. Workflow management software has been developed to aid in simplifying the replicable chaining of complex bioinformatics jobs, and cloud computing has emerged as a potential solution to the computational demands of this work. However, the capacity to effectively deploy these resources is limited by the expertise required to implement these solutions. Here, we develop Maloja, an easily deployed cloud workflow orchestrator. This tool interprets existing scientific workflows written in Snakemake and deploys them in appropriately scaled AWS cloud resources. We test the utility of this new toolset using previously published and custom built Snakemake workflows for ecological genomics tasks, revealing how this tool can facilitate the use of cloud resources without prior cloud architecture expertise.
Rational Design of Frontline Institutional Phage Cocktail for the Treatment of NosocomialEnterobacter cloacaeComplex Infections
Authors: Subedi Dinesh , Gordillo Altamirano Fernando , Deehan Rylee , Perera Avindya , Patwa Ruzeen , Kostoulias Xenia , Korneev Denis , Blakeway Luke , Macesic Nenad , Peleg Anton Y , Barr Jeremy J
Published: July 2024

Phage therapy is a promising strategy to treat antimicrobial-resistant infections. Currently, phage therapy applications span personalised treatments that are tailored for a given patient’s infection, through to the use of pre-established cocktails of virulent phages against clinically relevant pathogens. However, both approaches face challenges, with personalised phage therapy being time-consuming and requiring a phage match to a patient’s infection, while phage cocktails may not be effective against a patient’s specific strain. The Alfred Hospital in Melbourne, Australia has reported an ongoing outbreak of infections by theEnterobacter cloacaecomplex (ECC), a group of emerging multidrug-resistant pathogens responsible for considerable morbidity and mortality. Utilising the hospital’s strain collection, built over the last decade, we established an initial three-phage product with 54% ECC coverage that effectively reduced bacterial loads (>99%) in septicaemic mice. We then iteratively improved this product by enhancing phage killing efficiency using phage training and expanded host range through targeted phage isolation against low-coverage ECC strains. This iterative optimisation led to the creation of the productEntelli-02, containing five well characterised virulent phages that target clinical ECC strains through distinct bacterial cell surface receptors. Importantly,Entelli-02exhibits broad host coverage (99%) and efficacy (92%) against The Alfred Hospital’s ECC strain collection (n= 156). We produced this as a therapeutic-grade product, verified and endotoxin unit compliant, ready for use. This approach integrated academic phage research with clinical insights to produce the phage productEntelli-02as an institution-specific phage cocktail with frontline efficacy and on-demand availability.

In brief

We developed a phage product containing five phages with frontline potential to address infections caused by multidrug-resistantEnterobacter cloacaecomplex.
OPUS-TOMO: Deep Learning Framework for Structural Heterogeneity Analysis in Cryo-electron Tomography
Authors: Luo Zhenwei , Wang Qinghua , Ma Jianpeng
Published: July 2024

Structural heterogeneity due to the dynamic nature of macromoleculesin situpresents a significant challenge to structural determination by cryo-electron tomography (cryo-ET). In this paper, we present OPUS-TOMO, a deep learning framework for analyzing structural heterogeneity in cryo-ET data. The method adopts a convolutional Encoder-Decoder architecture that adeptly maps real-space subtomograms onto a smooth low-dimensional latent space, which captures the complete landscape of compositional and conformational variations of macromolecules in cryo-ET data. OPUS-TOMO also incorporates algorithms, including a per-particle 3D CTF model and a pose correction network, specifically for handling cryo-ET data. Applications of OPUS-TOMO to multiple real cryo-ET datasets confirm the outstanding capacities of the new method in characterizing structural heterogeneity. The software is available athttps://github.com/alncat/opusTOMO.
Glutathione Oxidation in Cerebrospinal Fluid as a Biomarker of Oxidative Stress in Amyotrophic Lateral Sclerosis
Authors: Pham Trong Khoa , Verber Nick , Turner Martin R , Malaspina Andrea , Collins Mark O. , Mead Richard J. , Shaw Pamela J.
Published: July 2024

Background

Oxidative stress is a key feature of several neurodegenerative diseases, including Amyotrophic Lateral Sclerosis (ALS). Identification of reliable biomarkers of oxidative stress would be beneficial for drug-target engagement studies.

Methods

We performed unbiased quantitative mass spectrometry (MS)-based analysis to measure changes in protein abundance and oxidation in cerebrospinal fluid (CSF) from a cohort of ALS patients and healthy controls at two time points (approximately four months apart) to capture disease progression. In addition, we developed a sensitive and targeted quantitative MS method to measure glutathione oxidation state in the same sets of CSF samples.

Results

Proteomic analysis of CSF revealed statistically significant changes in the abundance of several proteins, including CHIT1, CHI3L1, CHI3L2 and COL18A1 in ALS patients compared to healthy controls at both time points. Several sites of protein oxidation were significantly altered in ALS compared to healthy controls, and total levels of reversible protein oxidation were elevated in ALS patients. Given that glutathione oxidation could be a useful biomarker of oxidative stress, we also measured glutathione and its oxidation state in CSF in the same cohorts of samples. Total GSH (tGSH), GSSG levels and the GSSG/GSH ratio were significantly higher in the ALS than in the healthy control group for both time points. For the first visit, fold changes of tGSH, GSSG, and GSSG/GSH ratio in ALS compared to HC were 1.33 (p = 0.0215), 1.54 (p = 0.0041) and 1.80 (p = 0.0454), respectively. For the second visit, these values were 1.50 (p = 0.0143), 2.00 (p = 0.0018) and 2.14 (p = 0.0120), respectively. Furthermore, we found positive correlations between disease duration until the first visit and total glutathione (tGSH), GSSG and GSSG/GSH ratio. Finally, there was a strong positive correlation between the total intensity of reversibly oxidised proteins and the ratio of GSSG/GSH in ALS patients at both visits.

Conclusion

We propose that measuring levels of glutathione oxidation in CSF could act as a stratification biomarker to select ALS patients for antioxidant therapy and an approach to monitor the treatment response to therapeutic agents targeting oxidative stress.
Gene body methylation buffers noise in gene expression in plants
Authors: Zastąpiło Jakub , Emmerson Robyn , Mikheeva Liudmila A , Catoni Marco , Bechtold Ulrike , Zabet Nicolae Radu
Published: July 2024

Non-genetic variability in gene expression is an inevitable consequence of stochastic nature of processes driving transcription and translation. Largely thought to be deleterious to cell fitness, it is not uniform across the transcriptome. This implies the existence of (molecular) determinants affecting the degree of gene expression variability, although this remain poorly understood in multicellular systems. In this study, we found a link between gene body methylation and noise in gene expression inArabidopsis thaliana. More specifically, genes with high levels of noise show low levels of gene body methylation, while genes with lower level of noise in gene expression show higher level of gene body methylation. Most importantly, loss of CpG methylation in gene bodies lead to a significant number of genes displaying higher noise in gene expression. This could be compensated by low but significant gain of non-CpG methylation at promoters of certain genes. Overall, our results show that gene body methylation has a functional role and specifically controls the noise in gene expression for a large number of genes.
Role of vaccinia virus growth factor in stimulating the mTORC1-CAD axis of thede novopyrimidine pathway under different nutritional cues
Authors: Dsouza Lara , Pant Anil , Pope Blake , Yang Zhilong
Published: July 2024

Vaccinia virus (VACV), the prototype poxvirus, actively reprograms host cell metabolism upon infection. However, the nature and molecular mechanisms remain largely elusive. Given the diverse nutritional exposures of cells in different physiological contexts, it is essential to understand how VACV may alter various metabolic pathways in different nutritional conditions. In this study, we established the importance ofde novopyrimidine biosynthesis in VACV infection. We elucidated the significance of vaccinia growth factor (VGF), a viral early protein and a homolog of cellular epidermal growth factor, in enabling VACV to phosphorylate the key enzyme CAD of thede novopyrimidine pathway at serine 1859, a site known to positively regulate CAD activity. While nutrient-poor conditions typically inhibit mTORC1 activation, VACV activates CAD via mTORC1-S6K1 signaling axis, in conditions where glutamine and asparagine are absent. However, unlike its cellular homolog, epidermal growth factor (EGF), VGF peptide alone in the absence of VACV infection has minimal ability to activate CAD, suggestive of the involvement of other viral factor(s) and differential functions to EGF acquired during poxvirus evolution. Our research provides a foundation for understanding the regulation of a significant metabolic pathway, namely,de novopyrimidine synthesis during VACV infection, shedding new light on viral regulation under distinct nutritional environments. This study not only has the potential to contribute to the advancement of antiviral treatments but also improve the development of VACV as an oncolytic agent and vaccine vector.

Importance

Our research provides new insights into how VACV alters the mTORC1-CAD signaling axis under different nutritional cues. The identification of how VACV regulates a major enzyme, CAD, within thede novopyrimidine synthesis pathway, establishes a molecular mechanism for determining how VACV reshapes this essential pathway, necessary for facilitating efficient VACV replication. We further emphasize that, despite nutrient-poor conditions, which typically inhibit mTORC1 activation, VACV can stimulate mTORC1. We identify its early growth factor, VGF, as an important factor for this stimulation of mTORC1 and its downstream effector CAD, revealing a new mechanism for how VACV sustains mTORC1-CAD axis activation under these nutrient deficient conditions. This work provides fresh insights into the molecular mechanisms of mTORC1-CAD regulation, which has the potential to be utilized to enhance VACV as an oncolytic tool, vaccine vector and aid in the development of antiviral drugs.
TheArabidopsis thalianacore splicing factor PORCUPINE/SmE1 requires intron-mediated expression
Authors: Dikaya Varvara , Rojas-Murcia Nelson , Benstein Ruben M. , Eiserhardt Wolf L. , Schmid Markus
Published: July 2024

Plants are prone to genome duplications and tend to preserve multiple gene copies. This is also the case for the genes encoding the Sm proteins ofArabidopsis thaliana(L). The Sm proteins are best known for their roles in RNA processing such as pre-mRNA splicing and nonsense-mediated mRNA decay. In this study, we have taken a closer look at the phylogeny and differential regulation of the SmE-coding genes found inA. thaliana,PCP/SmE1, best known for its cold-sensitive phenotype, and its paralog,PCPL/SmE2. The phylogeny of thePCPhomologs in the green lineage shows thatSmEduplications happened multiple times independently in different plant clades and that the duplication that gave rise toPCPandPCPLoccurred only in the Brassicaceae family. Our analysis revealed thatA. thalianaPCP and PCPL proteins, which only differ in two amino acids, exhibit a very high level of functional conservation and are able to perform the same function in the cell. However, our results indicate thatPCPis the prevailing copy of the twoSmEgenes inA. thalianaas it is more highly expressed and that the main difference betweenPCPandPCPLresides in their transcriptional regulation, which is strongly linked to intronic sequences.
Gravitational positivity for phenomenologists: Dark gauge boson in the swampland
Authors: Aoki Katsuki , Noumi Toshifumi , Saito Ryo , Sato Sota , Shirai Satoshi , Tokuda Junsei , Yamazaki Masahito
Published: July 2024

The gravitational positivity bound gives quantitative “swampland” constraints on low-energy effective theories inside theories of quantum gravity. We give a comprehensive discussion of this bound for those interested in applications to phenomenological model building. We present a practical recipe for deriving the bound, and discuss subtleties relevant for realistic models. As an illustration, we study the positivity bound on the scattering of the massive gauge bosons in the Higgs/Stückelberg mechanism. Under certain assumptions on gravitational amplitudes at high energy, we obtain a lower bound mV≳ΛUV2/gMPl on the gauge boson mass mV, where g is the coupling constant of the gauge field, MPl is the reduced Planck mass and ΛUV is the ultraviolet cutoff of the effective field theory. This bound can strongly constrain new physics models involving a massive gauge boson. We also discuss how the bound depends on our high-energy assumptions.

Published by the American Physical Society
2024
Sound in a bubbly hybrid neutron star
Authors: Kerbikov B. O. , Lukashov M. S.
Published: July 2024

Increasingly precise astrophysical observations of the last decade in combination with intense theoretical studies allow for drawing a conclusion about potential quark matter presence in neutron stars’ interiors. Quark matter may form the neutron star inner core or be immersed in the form of bubbles, or droplets. We consider the second scenario and demonstrate that even a small fraction of quark matter bubbles can lead to a high nonlinearity of the sound wave. Below the bubble resonant frequency the sound speed is lower than the ambient value. At the resonance it sharply grows. The peak is constrained by viscous dissipation. Above the resonance the speed exceeds the pure neutron star matter value. The dispersion equation for the bubbly neutron star compressibility is derived.

Published by the American Physical Society
2024
Adaptive Trotterization for Time-Dependent Hamiltonian Quantum Dynamics Using Piecewise Conservation Laws
Authors: Zhao Hongzheng , Bukov Marin , Heyl Markus , Moessner Roderich
Published: July 2024

Digital quantum simulation relies on Trotterization to discretize time evolution into elementary quantum gates. On current quantum processors with notable gate imperfections, there is a critical trade-off between improved accuracy for finer time steps, and increased error rate on account of the larger circuit depth. We present an adaptive Trotterization algorithm to cope with time dependent Hamiltonians, where we propose a concept of to estimate errors in the time evolution between two (nearby) points in time; these allow us to bound the errors accumulated over the full simulation period. They reduce to standard conservation laws in the case of time independent Hamiltonians, for which we first developed an adaptive Trotterization scheme [H. Zhao , Making Trotterization adaptive and energy-self-correcting for NISQ devices and beyond, .]. We validate the algorithm for a time dependent quantum spin chain, demonstrating that it can outperform the conventional Trotter algorithm with a fixed step size at a controlled error.

Published by the American Physical Society
2024
Inherent Thermal-Noise Problem in Addressing Qubits
Authors: Simbierowicz Slawomir , Borrelli Massimo , Monarkha Volodymyr , Nuutinen Ville , Lake Russell E.
Published: July 2024

Qubit-specific measurement in a superconducting quantum processor requires physical interconnects that traverse 4 orders of magnitude in temperature from 293 K to 10 mK. Although the quantum processor can be thermalized and shielded from electromagnetic noise, the interconnects themselves introduce an unavoidable remote heat bath that causes decoherence of quantum states. In the present work, we report quantitative and device-independent measurements of the power radiated to the quantum processor from its control lines. Our results have been obtained using a calibrated bolometer that operates within a millikelvin environment with time-resolved measurement capability. In the limit of zero applied power, the noise power emitted to the quantum processor is equivalent to that of a blackbody with temperature 63–71 mK for the prototypical drive lines in the study. Experimentally, we increase the applied power of a simulated control signal to map out the resulting temperature rise and thermal time constant of five prototypical drive-line varieties. We input the data to an open quantum system model to demonstrate the trade-off between dissipated signal power, transmon-qubit lifetime, pure dephasing, gate fidelity, and the implied decoherence rates due to self-heating during microwave operations. Beyond explaining dephasing rates observed in the literature, our work sets the stage for accurate noise modeling in novel quantum computer interfacing methods due to our device-agnostic approach.

Published by the American Physical Society
2024
“Target” versus “Non-target”: how free gift influences surplus food purchase intention
Authors: Zhang Yuexian , Wang Xueying
Published: July 2024

Purpose

Free gifts have become a commonly used marketing strategy. Nevertheless, whether free gifts can and how this strategy promotes the surplus food purchase intention remain a debated topic. This paper attempts to evaluate the effectiveness of offering free gifts (target and non-target products) in enhancing the purchase intention associated with surplus food.

Design/methodology/approach

Categorically, Studies 1 to 4 were performed to analyze the impact of the free gift on the surplus food purchase intention, explore the mediating role of perceived quality uncertainty and examine the moderating role of blind-box design and mental simulation.

Findings

The study findings indicate that the provision of non-target products as a free gift exerts a more pronounced influence on surplus food purchase intention as compared to offering a target product as a free gift. Evidently, perceived quality uncertainty serves as a mediating role, whereas blind-box design and mental simulation are identified as moderators in this process.

Originality/value

This paper compares the influences of various types of free gifts, namely target and non-target products, on surplus food purchase intention through perceived quality uncertainty, thereby enhancing the existing comprehension of free gifts and surplus food purchase intention. In addition, this article extends the boundary conditions of free gifts by investigating the moderating influence of blind-box design and mental simulation.