bluuebunny/crossref_metadata_2025_split huggingface dataset:
Target gene responses differ when transcription factor levels are acutely decreased by nuclear export versus degradation
Authors: McGehee James , Stathopoulos Angelike 
Published: May 2024

ABSTRACTDefining the time of action for morphogens requires tools capable of temporally controlled perturbations. To study how the transcription factor Dorsal affects patterning of theDrosophilaembryonic dorsal-ventral axis, we used two light-inducible tags that result in either nuclear export or degradation of Dorsal when exposed to blue light. Nuclear export of Dorsal results in loss of expression for the high threshold, ventrally-expressed target genesnail(sna) but retention of the low threshold, laterally-expressed target geneshort-gastrulation(sog). In contrast, degradation of Dorsal results in retention ofsna,loss ofsog, and lower nuclear levels than when Dorsal is exported from the nucleus. To elucidate how nuclear export results in loss ofsnabut degradation does not, we investigated Dorsal kinetics using photobleaching and found it reenters the nucleus even under conditions of blue-light when export is favored. The associated kinetics of being imported and exported continuously are likely responsible for loss ofsnabut, alternatively, can supportsog. Collectively, our results show that this dynamic patterning process is influenced by both Dorsal concentration and nuclear retention.SUMMARY STATEMENTThis study shows how optogenetic tools can be used to determine how a transcription factor’s levels and nuclear retention impact a dynamic patterning process.
Reprogramming SREBP1-dependent lipogenesis and inflammation in high-risk breast with licochalcone A: a novel path to cancer prevention
Authors: Hajirahimkhan Atieh , Bartom Elizabeth T. , Chung Carolina H , Guo Xingyu , Berkley Kyli , Lee Oukseub , Chen Ruohui , Cho Wonhwa , Chandrasekaran Sriram , Clare Susan E. , Khan Seema A. 
Published: May 2024

AbstractBackgroundAnti-estrogens have had limited impact on breast cancer (BC) prevention. Novel agents with better tolerability, and efficacy beyond estrogen receptor (ER) positive BC are needed. We studied licochalcone A (LicA) for ER-agnostic BC prevention.MethodsWe evaluated antiproliferative effects of LicA in seven breast cell lines and its suppression of ER+ and ER− xenograft tumors in mice. High-risk human breast tissue was treated with LicAex vivo, followed by RNA sequencing and metabolism flux modeling. Confirmatory testing was performed in an independent specimen set and ER+/− BC cell lines using NanoString metabolic panel, proteomics, western blots, and spatiotemporally resolved cholesterol quantification in single cells.ResultsLicA suppressed proliferationin vitroand xenograft tumor growthin vivo. It downregulated pivotal steps in PI3K-AKT-SREBP1-dependent lipogenesis, suppressed PI3K and AKT phosphorylation, SREBP1 protein expression, and cholesterol levels in the plasma membrane inner leaflet, to the levels in normal breast cells. LicA also suppressed prostaglandin E2 synthesis and PRPS1-catalyzedde novonucleotide biosynthesis, stalling proliferation; further evident by reduced MKI67 and BCL2 proteins.ConclusionsLicA targets SREBP1, a central regulator of lipogenesis and immune response, reducing pro-tumorigenic aberrations in lipid homeostasis and inflammation. It is a promising non-endocrine candidate for BC prevention.
Pseudomonas syringaesocially-induced swimming motility requires the molybdenum cofactor
Authors: Yang Zichu , Swingle Bryan 
Published: May 2024

AbstractSocial interactions among bacteria can induce behaviors that affect their fitness and influence how complex communities assemble. Here we report a new socially-induced motility behavior that we refer to as baited expansion inPseudomonas syringaepv. tomato DC3000 (PstDC3000), a plant pathogenic bacterium. We foundPstDC3000 displayed strongly-induced swimming motility towards nearby colonies ofDickeya dianthicolaorEscherichia coli. We developed a controlled system to visualize and characterize the development of baited expansion. Our results provide evidence that baited expansion behavior occurs in response to a chemical gradient established and maintained by the bait colony. We also found this behavior correlated with distinct transcriptional profiles and identified molybdenum cofactor as a crucial factor in facilitating the baited expansion behavior.
Neuraminidase 1 regulates the cellular state of microglia by modulating the sialylation of Trem2
Authors: Fremuth Leigh Ellen , Hu Huimin , van de Vlekkert Diantha , Annunziata Ida , Weesner Jason Andrew , Gomero Elida , d’Azzo Alessandra 
Published: May 2024

SummaryNeuraminidase 1 (Neu1) cleaves terminal sialic acids from sialoglycoproteins in endolysosomes and at the plasma membrane. As such, Neu1 regulates immune cells, primarily those of the monocytic lineage. Here we examined how Neu1 influences microglia by modulating the sialylation of full-length Trem2 (Trem2-FL), a multifunctional receptor that regulates microglial survival, phagocytosis, and cytokine production. When Neu1 was deficient/downregulated, Trem2-FL remained sialylated, accumulated intracellularly, and was excessively cleaved into a C-terminal fragment (Trem2-CTF) and an extracellular soluble domain (sTrem2), enhancing their signaling capacities. Sialylated Trem2-FL (Sia-Trem2-FL) did not hinder Trem2-FL–DAP12–Syk complex assembly but impaired signal transduction through Syk, ultimately abolishing Trem2-dependent phagocytosis. Concurrently, Trem2-CTF–DAP12 complexes dampened NFκB signaling, while sTrem2 propagated Akt-dependent cell survival and NFAT1-mediated production of TNFα and CCL3. Because Neu1 and Trem2 are implicated in neurodegenerative/neuroinflammatory diseases, including Alzheimer disease (AD) and sialidosis, modulating Neu1 activity represents a therapeutic approach to broadly regulate microglia-mediated neuroinflammation.
Rapid detection, quantification and speciation ofLeishmaniausing real-time PCR and DNA sequencing at the rRNA Internal Transcribed Spacer 2
Authors: Paun Andrea , Grigg Michael E. 
Published: May 2024

AbstractThe ability to discriminate infection between closely relatedLeishmaniaspecies within theVianniaspecies complex, specificallyL. braziliensis, L. guyanensisandL. panamensisis critical to inform the clinical diagnosis and determine the most efficacious treatment modality. We designed a nested primer set targeting the rRNA Internal Transcribed Spacer 2 (ITS2), located on Chromosome 27, to distinguish among all human infectiveLeishmaniaspecies. Separate nested and single primer pairs were developed for conventional and quantitative PCR approaches respectively. Species-specific single nucleotide polymorphisms and indels located within the PCR products were identified by Sanger sequencing. This single locus approach provides a sensitive and specific platform to identify the species ofLeishmaniacausing infection.
Enhancing tumor-infiltrating T cells with an exclusive fuel source
Authors: Miller Matthew L. , Thauland Timothy J. , Nagarajan Rina , Zuo Wenqi Ellen , Moreno Lastre Miguel A. , Butte Manish J. 
Published: May 2024

SummarySolid tumors harbor immunosuppressive microenvironments that inhibit tumor-infiltrating lymphocytes (TILs) through the voracious consumption of glucose. We sought to restore TIL function by providing them with an exclusive fuel source. The glucose disaccharide cellobiose, which is the building block of cellulose, contains a β-1,4-glycosidic bond that that animals (or their tumors) cannot hydrolyze, but microbes have evolved enzymes to catabolize cellobiose into useful glucose. We equipped mouse T cells and human CAR-T cells with two proteins enabling import and hydrolysis of cellobiose and demonstrated that cellobiose supplementation during glucose withdrawal restores key anti-tumor T-cell functions: viability, proliferation, cytokine production, and cytotoxic killing. Engineered T cells offered cellobiose suppress murine tumor growth and prolong survival. Offering exclusive access to a natural disaccharide is a new tool that augments cancer immunotherapies. This approach could be used to answer questions about glucose metabolism across many cell types, biological processes, and diseases.
Opioid Modulation of Differential Gene Expression and Neuronal Differentiation in the Ventricular-Subventricular Zone of Adult Male Zebra Finches
Authors: Din Uzma , Banerjee Sourav , Iyengar Soumya 
Published: May 2024

1AbstractThe endogenous opioid system modulates diverse functions including pain, physiological functions and motivation. We had earlier demonstrated an increase in cell proliferation in the neurogenic niche of adult male zebra finches, following administration of the general opioid antagonist, naloxone. Since the mechanisms underlying opioid modulation of neurogenesis are poorly understood, we have investigated the molecular mechanisms underlying cell proliferation differentiation induced by the opioid system. Systemic naloxone or vehicle administration in adult male birds was followed by a whole transcriptome microarray assay of the ventricular-subventricular zone (V-SVZ). The analysis revealed 26 differentially expressed transcripts (expression fold change ≥ 1.5), encoding genes important for neuronal functions. The transcriptomics analysis using microarray identified a significant increase in the expression of precursor miRNAtgu-mir-124-201transcript following inhibition of opioid receptors by naloxone. Our results suggested that the administration of naloxone triggers an increase in the expression of the pro-differentiating microRNA, miR-124, in the brains of adult zebra finches. Using quantitative real-time PCR, we found that the expression of miR-124-3p was higher in the V-SVZ of naloxone-treated versus control birds. Furthermore, the density of neuroblasts was higher in the ventral V-SVZ adjacent to the striatal nucleus Area X, but not in the V-SVZ above the pallial nucleus, HVC, both of which are involved in singing. Since miR-124 targets signalling pathways important for neuronal proliferation and differentiation, our findings suggest that microRNA-124 may be involved in the increase in neurogenesis in adult songbirds induced by altering opioid modulation.
Investigating neurometabolite changes in response to median nerve stimulation
Authors: Houlgreave Mairi S. , Dyke Katherine , Berrington Adam , Jackson Stephen R. 
Published: May 2024

AbstractBackgroundRhythmic median nerve stimulation (MNS) at 10Hz has been shown to cause a substantial reduction in tic frequency in individuals with Tourette Syndrome. The mechanism of action is currently unknown, but is hypothesised to involve entrainment of oscillations within the sensorimotor cortex.ObjectiveWe used functional magnetic resonance spectroscopy (fMRS) to explore the dynamic effects of MNS on neurometabolite concentrations.MethodsHere, we investigated the effects of rhythmic and arrhythmic 10Hz MNS on glutamate (Glu) and GABA concentrations in the contralateral sensorimotor cortex in 15 healthy controls, using a blocked fMRS design. We used a Mescher-Garwood-semi-localised by adiabatic selective refocusing (MEGA-sLASER) sequence at 7T.ResultsOur results show no difference in the difference-from-baseline measures between the two stimulation conditions. Looking at the effect of MNS over both conditions there is a trend for an initial increase in Glu/tCr (total creatine) followed by a decrease over time, whereas GABA/tCr decreased during each stimulation block.ConclusionThese results suggest that despite entrainment of oscillations during rhythmic MNS, there are no significant differences in the tonic neuromodulatory effects of rhythmic and arrhythmic stimulation. The reduction in glutamate over the course of stimulation may reflect a decrease in glutamatergic firing due to adaptation. This may make it less likely that an involuntary movement is generated during continuous stimulation.
Assessing the potential antifungal resistance risk from dual use of a mode of action in agriculture and medical treatment of human pathogens
Authors: Paveley Neil , van den Bosch Frank , Grimmer Michael 
Published: May 2024

ABSTRACTA mechanistic basis is described for assessment of resistance risk to medical anti-fungal treatments from agricultural use of fungicides of the same mode of action. The following need to occur in landscape environments for a risk to be posed by ‘dual use’: (i) emergence, whereby a resistant strain emerges by mutation and invasion, (ii) selection, whereby a mutation conferring a fitness advantage is selected for in the presence of fungicide, and (iii) exposure of humans to resistant strains from the landscape, potentially resulting in invasive fungal infection (IFI). We identify 20 human fungal pathogens for which there is evidence that all three processes above could, in principle, occur. A model is derived for quantitative analysis to explore what determines resistance emergence and selection in human pathogens in landscape environments. Emergence and selection were particularly affected by fitness cost associated with the resistance mutation(s) and fungicide concentration.Emergence was also determined by the amount of pathogen reproduction (related to pathogen population size). The findings were related to an example case of observational data from the Netherlands for Aspergillus fumigatus. The analysis supports previous work that compost, including bulb waste, is towards the high-risk end of the spectrum for this species. Agricultural soils, non-agricultural land and grassland were lower risk. More generally, across species, the model output suggests that if fungicide resistance is associated with even a small fitness cost, then environments with low fungicide concentrations, such as field soils and semi-natural environments (e.g. woodland), may not be conducive to resistance emergence or selection.
Parallel Evolution of Salinity Tolerance inArabidopsis thalianaAccessions from Cape Verde Islands
Authors: Rivas Félix J Martínez , Wozny Dorothee , Xue Zeyun , Gilbault Elodie , Sapir Thomas , Rouille Melissa , Ricou Antony , Medina Joaquín , Noël Laurent D. , Lauber Emmanuelle , Voxeur Aline , Loudet Olivier , Clément Gilles , Jiménez-Gómez Jose M 
Published: May 2024

AbstractSoil salinization poses a significant threat to crop production impacting one fifth of all cultivated land. The Cape Verde Islands are located 600 km from the coast of Africa and are characterized by high salinity soils and inland water sources.In this study we find thatArabidopsis thalianaplants native to these islands accumulate a metabolite that protects them from salt stress. We partially characterized this metabolite as glucuronyl-mannose. We find that the ability to produce glucuronyl-mannose evolved independently in two different islands from the same archipelago through mutations in the same gene, an alpha glycosidase protein that we named GH38cv. These cases of parallel evolution suggest positive selection towards the increase of salt tolerance with low fitness costs. Indeed, plants carrying derived alleles of GH38cv do not present growth defects or low defenses under normal conditions, but show better germination rates, longer roots and better hydric status than non-mutated plants when exposed to salt stress. These findings provide a knowledge-based method to develop salt resilient crops using natural mechanisms, which could be attractive both to conventional and organic agriculture.
SpatialDiffusion: Predicting Spatial Transcriptomics with Denoising Diffusion Probabilistic Models
Authors: Khan Sumeer Ahmad , Lagani Vincenzo , Lehmann Robert , Kiani Narsis A. , Gomez-Cabrero David , Tegner Jesper 
Published: May 2024

AbstractSpatial Transcriptomics (ST) allows deep characterization of the 2D organization of expression data within tissue slices. The ST technology provides a tissue contextualization of deep single-cell profiles. Recently, numerous computational and machine learning methods have addressed challenges such as data quality, augmentation, annotation, and the development of integrative platforms for data analysis. In contrast, here we ask whetherunseen spatial transcriptomics data can be predicted and if we can interpolate novel transcriptomic slices. To this end, we adopt a denoising diffusion probabilistic-based model (DDPM) todemonstrate the learning ofgenerative ST models for several tissues. Furthermore, our generative diffusion model interpolates (predicts) unseen slices located “between” the collected finite number of ST slices. This methodology set the stage for learning predictive deep 3D models of tissues from a finite number of spatial transcriptomics slices, thus harboring the advent of AI-augmented spatial transcriptomics.
Thermodynamics Underpinning the Microbial Community-Level Nitrogen Networks
Authors: Seto Mayumi , Sasaki Risa , Ooka Hideshi , Nakamura Ryuhei 
Published: May 2024

AbstractNitrogen species often serve as crucial electron donors or acceptors in microbial catabolism, enabling the synthesis of adenosine triphosphate (ATP). Although theoretically any nitrogen redox reactions could be an energy source, it remains unclear why specific reactions are predominantly utilized. This study evaluates energetically superior reactions from 988 theoretically plausible combinations involving 11 nitrogen species, oxygen gas, hydrogen ion, and water. Our analysis of the similarity between this model-based energetically superior network and the actual microbial community-level nitrogen network, reconstructed as a combination of enzymatic reactions, showed increased link overlap rates with thermodynamic weighting on reaction rates. In particular, existing microbial reactions involving solely nitrogen species and additionally oxygen, such as anaerobic ammonia oxidation (ANAMMOX) and complete and partial nitrification, were frequently identified as energetically superior among the examined reactions. The alignment of these reactions with thermodynamically favorable outcomes underscores the critical role of thermodynamics not only in individual metabolic processes but also in shaping the broader network interactions within ecosystems, consequently affecting biodiversity and ecological functions.Significance StatementThis study advances our understanding of how thermodynamics governs energy metabolism at the community level within microbial ecosystems by systematically analyzing 988 potential redox reactions involving inorganic nitrogen species, oxygen gas, hydrogen ion, and water. We uncover that existing microbial reactions, such as anaerobic ammonia oxidation (ANAMMOX) and nitrification, stand out as energetically superior over other examined reactions. The robust alignment between model-predicted energetically favorable reactions and actual microbial nitrogen reactions underscores the predictive power of thermodynamic principles, even in ecological networks. Our findings extend the traditional applications of thermodynamics in biology, highlighting how thermodynamic constraints shape ecological networks and influence biodiversity and ecosystem functions in natural ecosystems.
Pro-survival roles for p21(Cip1/Waf1) in Non-Small Cell Lung Cancer
Authors: Cutty SJ , Hughes FA , Ortega-Prieto P , Desai S , Thomas P , Fets LV , Secrier M , Barr AR 
Published: May 2024

AbstractQuiescence is a reversible state of proliferative arrest, distinct from senescence. While cancer is a disease of dysregulated proliferation, cancer cells can retain the ability to enter quiescence which confers advantages to tumour cells by protecting them from chemotherapy or by allowing metastasis to distant sites. Multiple mechanisms exist to induce and maintain quiescence that are not yet fully understood. Here, we show that high expression of the CDK inhibitor p21Cip1/Waf1correlates with a poor prognosis inTP53wild-type, but notTP53mutant, non-small cell lung cancer (NSCLC) patients. Using quantitative single-cell imaging of genetically-engineered NSCLC reporter cell lines, we show thatTP53wild-type NSCLC cells can enter a p21-dependent spontaneous quiescent state, downstream of replication stress. Furthermore, p21 expression confers survival advantages toTP53wild-type NSCLC cells, both under normal proliferation and in response to chemotherapy. We also show that p21 can promote tumour relapse by allowing cells to recover from both G1 and G2 arrest states after drug removal. Together, our data suggest that targeting p21 function inTP53wild-type tumours could lead to better outcomes for chemotherapy treatment in NSCLC patients.Statement of SignificanceWe show thatTP53WT Non-Small Cell Lung Cancer cells can enter a p21-dependent spontaneous quiescent state and that p21 maintains the viability of NSCLC cells, is chemoprotective and can promote tumour relapse.
Paenilamicins from the honey bee pathogenPaenibacillus larvaeare context-specific translocation inhibitors of protein synthesis
Authors: Koller Timm O. , Berger Max J. , Morici Martino , Paternoga Helge , Bulatov Timur , Di Stasi Adriana , Dang Tam , Mainz Andi , Raulf Karoline , Crowe-McAuliffe Caillan , Scocchi Marco , Mardirossian Mario , Beckert Bertrand , Vázquez-Laslop Nora , Mankin Alexander , Süssmuth Roderich D. , Wilson Daniel N. 
Published: May 2024

AbstractThe paenilamicins are a group of hybrid non-ribosomal peptide-polyketide compounds produced by the honey bee pathogenPaenibacillus larvaethat display activity against Gram-positive pathogens, such asStaphylococcus aureus. While paenilamicins have been shown to inhibit protein synthesis, their mechanism of action has remained unclear. Here, we have determined structures of the paenilamicin PamB2 stalled ribosomes, revealing a unique binding site on the small 30S subunit located between the A- and P-site tRNAs. In addition to providing a precise description of interactions of PamB2 with the ribosome, the structures also rationalize the resistance mechanisms utilized byP. larvae. We could further demonstrate that PamB2 interferes with the translocation of mRNA and tRNAs through the ribosome during translation elongation, and that this inhibitory activity is influenced by the presence of modifications at position 37 of the A-site tRNA. Collectively, our study defines the paenilamicins as a new class of context-specific translocation inhibitors.
Lymphostatin: Structure of a large multi-functional virulence factor
Authors: Griessmann Matthias , Rasmussen Tim , Flegler Vanessa J. , Kraft Christian , Schneider Ronja , Spantzel Lukas , Stevens Mark P. , Börsch Michael , Böttcher Bettina 
Published: May 2024

SummaryEnteropathogenic and EnterohaemorrhagicEscherichia coliare enteric pathogens of global importance and human infections can be life-threatening. Lymphostatin is a key virulence factor of these bacteria, being required for intestinal colonisation and a potent inhibitor of the mitogen- and antigen-activated proliferation of lymphocytes and proinflammatory responses. In some strains, it also mediates adherence to host cells and influences actin nucleation at sites of attachment. This 365 kDa protein requires glycosyltransferase and cysteine protease motifs for activity against lymphocytes, but high-resolution structural information has proven elusive and the molecular mechanisms by which it acts remain unclear. Here, we describe the structure of lymphostatin from the prototype O127:H6 enteropathogenicE. colistrain determined by electron cryo-microscopy. Our results reveal two glycosyltransferase domains, one PaTox-like protease domain, an ADP-ribosyltransferase domain, and a delivery domain. Long linkers act to hold these domains together. These linkers occlude the catalytic sites of the N-terminal glycosyltransferase and protease domains. In this dormant state, lymphostatin binds to HEK-293T cells, where it forms large clusters before being taken up and sequestered into cytosolic foci. With more functional domains than any other known large bacterial toxin, lymphostatin can be regarded as the multifunctional Swiss army knife of pathogenicEscherichia coli, enabling complex interactions with the host cells in different environments.