bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ionizable networks mediate pH-dependent allostery in SH2 signaling proteins
Authors: Van Dyck Papa Kobina , Piszkin Luke , Gorski Elijah A. , Nascimento Eduarda Tartarella , Abebe Joshua A. , Hoffmann Logan M. , Peng Jeffrey W. , White Katharine A. 
Published: August 2024

IntroductionTransient intracellular pH dynamics1regulate mammalian proliferation2,3, migration4, and differentiation5. However, for many pH-dependent cell processes, the molecular mediators are unknown6. Prior work identified histidine residues as molecular switches in pH-sensitive proteins, but how other ionizable residues contribute to pH-dependent protein allostery is understudied. Here, we develop anin silicocomputational pipeline to identify putative pH-sensitive proteins and their molecular mechanisms. We first apply this pipeline to SHP2, a known pH-sensitive signaling protein with an uncharacterized molecular mechanism. We show wild-type SHP2 phosphatase activity is pH-sensitivein vitroand in cells, and mutation of identified H116 and E252 to non-titratable alanine residues abolishes pH-sensitive function. We also show that c-Src is a previously unrecognized pH-dependent kinase, and mutation of the identified ionizable network again abolishes pH-sensitive activity. Constant pH molecular dynamics simulations support a conserved allosteric mechanism of pH-dependent binding of inhibitory SH2 domains to the functional catalytic domains of SHP2 and c-Src. We apply our computational pipeline across SH2 domain-containing signaling proteins and identify evolutionarily conserved putative pH-sensing networks. Our results reveal that pH is an allosteric regulator of SH2 domain-containing signaling proteins providing insight into normal pH-dependent cell biology and diseases where pHi is dysregulated, such as cancer.
Conventional therapy induces tumor immunoediting and modulates the immune contexture in colorectal cancer
Authors: Fotakis Georgios , Rieder Dietmar , Loncova Zuzana , Carollo Sandro , Klieser Eckhard , Neureiter Daniel , Huemer Florian , Hoegler Sandra , Tomberger Martina , Krogsdam Anne , Kenner Lukas , Ziegler Paul K. , Greil Richard , Weiss Lukas , Trajanoski Zlatko 
Published: August 2024

AbstractBackgroundCancer immunotherapies for patients with colorectal cancer (CRC) continue to lag behind other solid cancer types with the exception of 4% of patients with microsatellite-instable tumors. Thus, there is an urgent need to broaden the clinical benefit of checkpoint blockers to CRC by combining conventional therapies to sensitise tumors to immunotherapy. However, the impact of conventional drugs on immunoediting, potentially promoting the positive selection of less immunogenic variants, and on the tumor immune contexture in CRC, remain elusive.MethodsWe performed comprehensive multimodal profiling using longitudinal samples from metastatic CRC patients undergoing neoadjuvant therapy with mFOLFOX6 and Bevacizumab. Exome-sequencing, RNA-sequencing and multiplexed immunofluorescence imaging was carried out on tumor samples obtained before and after therapy and the data was analysed using established methods. The results of the analysis were extrapolated to publicly available datasets (TCGA and CPTAC). In order to identify a surrogate marker, an explainable artificial intelligence method was developed using a transformer-based analytical pipeline for the identification of features in Hematoxylin and Eosin (H&E) images associated with specific biological processes, followed by manual evaluation of highly informative tiles by a pathologist.ResultsMutational profiles were highly modified and the level of genetic intertumoral heterogeneity between patients varied following treatment. Evolutionary analysis indicated eradication of some clones and dominant clonal prevalence of others, supporting the notion of pharmacologically-induced cancer immunoeditin. Post treatment samples showed upregulation of HLA class II genes, activation of differentiation and stemness pathways, and changes in the consensus molecular subtypes. The tumor immune contexture was characterised by increased densities of CD8+ and CD4+ T cells, but reduced T cell-tumor cell interactions (and increased T cell exhaustion. The AI-guided analyses of the H&E images pinpointed extracellular mucin deposits associated with stemness genes, suggesting a surrogate marker for routine pathological evaluation.ConclusionsConventional therapy induces immunoediting and modulates the immune contexture in metastatic CRC patients.
Latitudinal gradients in air density create “invisible topography” at sea level affecting animal flight costs
Authors: Shepard Emily L.C. , Garde Baptiste , Krishnan Krishnamoorthy , Fell Adam , Tatayah Vikash , Jones Carl G. , Cole Nik C. , Lempidakis Emmanouil 
Published: August 2024

SUMMARYRegional patterns in wind underpin the low-cost migratory flyways of billions of birds and insects1-3, but how large-scale changes in temperature affect flight is unknown. Flight costs should increase with rising temperatures, because lift decreases as density decreases, whereas weight remains unchanged. The effects of air density on flight costs are well-established in the context of high-altitude movements and migration4-7. Here, we examine the impact of air density on low-flying birds, in relation to seasonal, regional and global changes in temperature. Using multi-sensor loggers, we find that air density was the most important predictor of wingbeat frequency in red-tailed tropicbirds (Phaethon rubricauda) breeding year-round in Mauritius. Lower air densities in the Austral summer were associated with a small but significant increase in mean wingbeat frequency, which translated to an estimated 1-2% increase in flight costs. The variation in flight costs increased by an order of magnitude when considered in space, rather than time, with flight costs varying by ≥ 10 % across the tropicbird’s range. Changes in air density can therefore be an important determinant of flight costs even when birds are operating close to sea-level. Indeed, mapping air density at sea-level revealed that global temperature gradients cause effective altitude to vary by >2 km when considered as seasonal averages. This “invisible topography” at sea-level could have influenced the biogeography of flight morphologies and life-history traits.
Effective excitability captures network dynamics across development and phenotypes
Authors: Vinogradov Oleg , Giannakakis Emmanouil , Buendía Victor , Uysal Betül , Ron Shlomo , Weinreb Eyal , Schwarz Niklas , Lerche Holger , Moses Elisha , Levina Anna 
Published: August 2024

ABSTRACTNeuronal culturesin vitroare a versatile system for studying the fundamental properties of individual neurons and neuronal networks. Recently, this approach has gained attention as a precision medicine tool. Mature neuronal culturesin vitroexhibit synchronized collective dynamics called network bursting. If analyzed appropriately, this activity could offer insights into the network’s properties, such as its composition, topology, and developmental and pathological processes. A promising method for investigating the collective dynamics of neuronal networks is to map them onto simplified dynamical systems. This approach allows the study of dynamical regimes and the characteristics of the parameters that lead to data-consistent activity. We designed a simple biophysically inspired dynamical system and used Bayesian inference to fit it to a large number of recordings ofin vitropopulation activity. Even with a small number of parameters, the model showed strong inter-parameter dependencies leading to invariant bursting dynamics for many parameter combinations. We further validated this observation in our analytical solution. We found thatin vitrobursting can be well characterized by each of three dynamical regimes: oscillatory, bistable, and excitable. The probability of finding a data-consistent match in a particular regime changes with network composition and development. The more informative way to describe thein vitronetwork bursting is the effective excitability, which we analytically show to be related to the parameter-invariance of the model’s dynamics. We establish that the effective excitability can be estimated directly from the experimentally recorded data. Finally, we demonstrate that effective excitability reliably detects the differences between cultures of cortical, hippocampal, and human pluripotent stem cell-derived neurons, allowing us to map their developmental trajectories. Our results open a new avenue for the model-based description ofin vitronetwork phenotypes emerging across different experimental conditions.
Early immune response toCoccidioidesis characterized by robust neutrophil and fibrotic macrophage recruitment and differentiation
Authors: Miranda Nadia , Davalos Oscar A. , Sebastian Aimy , Rangel Margarita V. , Leon Nicole F. , Gorman Bria M. , Murugesh Deepa K. , Hum Nicholas R. , Loots Gabriela G. , Hoyer Katrina K. , Weilhammer Dina R. 
Published: August 2024

AbstractCoccidioidomycosis, or Valley fever, is an emerging respiratory disease caused by soil dwelling fungi of theCoccidioidesgenus that is expected to spread from the southwest into the central U.S. by 2050. While 60% of infections are asymptomatic, the other 40% of patients experience a range of symptoms, from self-limiting pneumonia to life-threatening disseminated disease. The immunological events that underlie the progression to severe disease remain under defined. Here, we probed the early immune response toCoccidioidesusing a high dose of an attenuated strain ofC. posadasiiin a mouse model of infection coupled with single-cell RNA sequencing. At 24 hours post-infection, robust immune infiltration is detected in the lung, marked by high levels of inflammatory PD-L1+neutrophils and fungal-contact dependent pro-fibrotic Spp1+macrophages. These findings elucidate the early dynamics of the host response toCoccidioidesand provide a deeper understanding of host-pathogen interactions in the lung.ImportanceBy examining early immune dynamics in the lungs, we uncover critical insights into how myeloid cells, particularly neutrophils and macrophages, are recruited and differentiated duringCoccidioidesinfection. The discovery of specific immune cell subsets, such as PD-L1+neutrophils and Spp1+macrophages, which are associated with inflammation and fibrosis, highlights potential targets for therapeutic intervention. These findings provide a deeper understanding of the host-pathogen interactions that occur duringCoccidioidesinfection, offering valuable directions for developing more effective treatments and preventive strategies against this increasingly prevalent disease.
Predicting peptide properties from mass spectrometry data using deep attention-based multitask network and uncertainty quantification
Authors: Tariq Usman , Saeed Fahad 
Published: August 2024

AbstractDatabase search algorithms reduce the number of potential candidate peptides against which scoring needs to be performed using a single (i.e. mass) property for filtering. While useful, filtering based on one property may lead to exclusion of non-abundant spectra and uncharacterized peptides – potentially exacerbating thestreetlighteffect. Here we presentProteoRift, a novel attention and multitask deep-network, which canpredictmultiple peptide properties (length, missed cleavages, and modification status) directly from spectra. We demonstrate thatProteoRiftcan predict these properties with up to 97% accuracy resulting in search-space reduction by more than 90%. As a result, our end-to-end pipeline is shown to exhibit 8x to 12x speedups with peptide deduction accuracy comparable to algorithmic techniques. We also formulate two uncertainty estimation metrics, which can distinguish between in-distribution and out-of-distribution data (ROC-AUC 0.99) and predict high-scoring mass spectra against correct peptide (ROC-AUC 0.94). These models and metrics are integrated in an end-to-end ML pipeline available athttps://github.com/pcdslab/ProteoRift.
Reexamining the essentiality of Pdi1 in yeast – APDI1knockout is viable inKomagataella phaffiiand still produces recombinant disulfide bonded proteins
Authors: Palma Arianna , Kowarz Viktoria , Gasser Brigitte 
Published: August 2024

AbstractProtein disulfide isomerase 1 (Pdi1) and Ero1 form the main oxidative folding axis in the endoplasmic reticulum (ER). Despite having additional PDI family members, Pdi1 has long ago been determined to be essential in baker’s yeast and this concept was inferred to other yeast species. In this study, we reexamine the gene essentiality of Pdi1 in the methylotrophic yeastKomagataella phaffii. Strikingly, the absence of Pdi1 does not cause lethality, but even allows for folding and secretion of heterologous proteins in a homogeneous redox state. Remarkably, while sensitivity to externally added folding stressors, such as tunicamycin and DTT is increased inpdi1Δ knock-out cells, in non-stressed growth conditions they do not display upregulation of folding stress markers, such as the master chaperone Kar2 or the unfolded protein response regulator Hac1, suggesting homeostatic adaptation.
A stimulus-computable rational model of habituation in infants and adults
Authors: Raz Gal , Cao Anjie , Saxe Rebecca , Frank Michael C. 
Published: August 2024

AbstractHow do we decide what to look at and when to stop looking? Even very young infants engage in active visual selection, looking less and less as stimuli are repeated (habituation) and regaining interest when novel stimuli are subsequently introduced (dishabituation). The mechanisms underlying these looking time changes remain uncertain, however, due to limits on both the scope of existing formal models and the empirical precision of measurements of infant behavior. To address this, we developed the Rational Action, Noisy Choice for Habituation (RANCH) model, which operates over raw images and makes quantitative predictions of participants’ looking behaviors. In a series of pre-registered experiments, we exposed infants and adults to stimuli for varying durations and measured looking time to familiar and novel stimuli. We found that these data were well captured by RANCH. Using RANCH’s stimulus-computability, we also tested its out-of-sample predictions about the magnitude of dishabituation in a new experiment in which we manipulated the similarity between the familiar and novel stimulus. By framing looking behaviors as rational decision-making, this work identified how the dynamics of learning and exploration guide our visual attention from infancy through adulthood.
S-adenosylmethionine metabolism buffering is regulated by glycine N-methyltransferase decrease via nuclear ubiquitin-proteasome system
Authors: Kashio Soshiro , Miura Masayuki 
Published: August 2024

AbstractMetabolic homeostasis is essential for survival; however, many studies have focused on the fluctuations of these factors. Furthermore, while metabolic homeostasis depends on the balance between the production and consumption of metabolites, there have been limited investigations into the mechanisms regulating their consumption. S-adenosylmethionine (SAM) metabolism has diverse functions, including methylation, polyamine biosynthesis, and transsulfuration, making its regulation and control crucial. Recent studies have revealed the feedback regulation of SAM production; however, the mechanisms governing its consumption are still poorly understood.In this study, we focused on the stability of SAM levels in the fat body (FB) ofDrosophila, which serves as a functional equivalent of the mammalian liver and adipose tissue, under conditions of SAM shortage, including nutrient deprivation. We found that glycine N-methyltransferase (Gnmt), a major SAM-consuming methyltransferase in the FB, decreased via the nuclear ubiquitin-proteasome system (UPS), along with the inhibition of SAM synthesis and starvation. Furthermore, the nuclear accumulation of Gnmt with age disrupts the mechanism that maintains a stable SAM level. Thus, the regulation of Gnmt levels through nuclear UPS-mediated degradation helps maintain SAM levels under SAM shortage conditions and during aging.Significance StatementS-adenosylmethionine (SAM) metabolism is crucial for diverse functions, which are mediated through methylation process. Although the feedback regulation of SAM production has been explored extensively, our understanding of the mechanism behind SAM consumption remains incomplete. Constant levels of SAM have been observed inDrosophilafat bodies even under conditions of SAM shortage, including nutrient deficiency and inhibition of SAM synthesis. SAM levels are controlled by the degradation of glycine N-methyltransferase (Gnmt), a cytosolic SAM-consuming enzyme, via the nuclear ubiquitin-proteasome system under conditions of SAM shortage. Additionally, the inhibition of Gnmt degradation by suppression of the nuclear UPS causes starvation tolerance. Considering that SAM accumulation promotes energy expenditurein vivo, the starvation-dependent mechanism of Gnmt degradation is important for energy homeostasis.
Quantitative Interpretation of Transverse Spin Relaxation by Translational Diffusion in Liquids Under Arbitrary Potentials
Authors: Okuno Yusuke 
Published: August 2024

AbstractIntermolecular spin relaxation by translational motion of spin pairs have been widely used to study properties of the biomolecules in liquids. Notably, solvent paramagnetic relaxation enhancement (sPRE) arising from paramagnetic cosolutes has gained attentions for various applications, including the structural refinement of intrinsically disordered proteins, cosolute-induced protein denaturation, and the characterization of residue-specific effective near-surface electrostatic potentials (ENS). Among these applications, the transverse sPRE rate known as Γ2has been predominantly been interpreted empirically as being proportional to <r-6>norm. In this study, we present a rigorous theoretical interpretation of Γ2that it is instead proportional to <r-4>normand provide explicit formula for calculating <r-4>normwithout any adjustable parameters. This interpretation is independent of the type or strength of interactions and can be broadly applied, including to the precise interpretation of ENS.
Activation and Evasion of the FEAR Pathway by RNA Viruses
Authors: Rex Emily A. , Seo Dahee , Embry Aaron , Arulanandam Rozanne , Spinelli Marcus M. , Diallo Jean-Simon , Gammon Don B. 
Published: August 2024

AbstractWe recently identified theFACT-ETS-1AntiviralResponse (FEAR) pathway as an interferon-independent innate immune response that restricts DNA virus replication and is countered by poxvirus-encoded A51R proteins (Rexet al., 2024,Nature Microbiology). The human FEAR pathway is mediated by the FACT complex, consisting of hSpt16 and SSRP1 subunits, that remodels chromatin to activate expression of the antiviral transcription factor, ETS-1. To counter this pathway, poxvirus A51R proteins tether SUMOylated hSpt16 subunits to microtubules to prevent ETS-1 expression. While these observations indicate a role for the FEAR pathway in DNA virus restriction, it was unclear if RNA viruses interact with this pathway. Here, we show that RNA viruses are also restricted by the FEAR pathway, yet encode mechanisms distinct from poxviruses to counter this response. We show vesicular stomatitis virus (VSV), a rhabdovirus, utilizes its matrix (M) protein to promote proteasome-dependent degradation of SUMOylated hSpt16 and to block ETS-1 nuclear import. Strains encoding mutant M proteins that cannot antagonize the FEAR pathway exhibit replication defects in human cells that can be rescued by hSpt16 or ETS-1 depletion. Moreover, FACT inhibitor treatment enhanced the replication of oncolytic VSV strains encoding defective M proteins in restrictive cancer cells, suggesting FEAR pathway inhibition may improve oncolytic virotherapy. Strikingly, we provide evidence that the inability of VSV M to degrade SUMOylated Spt16 in lepidopteran insect cells results in abortive infection, suggesting VSV-Spt16 interactions influence virus host range. Lastly, we show that human and murine paramyxovirus target SUMOylated Spt16 proteins for degradation in human and murine cells utilizing a conserved N-terminal motif in their accessory “C” proteins. Collectively, our study illustrates that DNA and RNA viruses have independently evolved diverse mechanisms to antagonize SUMOylated host Spt16 proteins, underscoring the physiological importance of the FEAR pathway to antiviral immunity.
On the relationship between serotype, chemotype and genotype for Cryptococcus spp. including a method for including polysaccharide structure in strain characterization
Authors: Wear Maggie P. , Greengo Seth , McConnell Scott , Xu Alan , Lopes Livia Liporagi , Majumdar Ananya , Casadevall Arturo 
Published: August 2024

Over the past eight decades the classification of cryptococcal strains has relied on the technologies available to discriminate among isolates, such as serology, exopolysaccharide (EPS) NMR, and most recently multi-locus sequencing, which yielded serotypes, chemotypes, and genotypes, respectively. However, as one method superseded the other, the relationship between classification schemes became uncertain, resulting in assumptions that have not been rigorously validated. Here we compared the serotype, chemotype, and genotype as defined by multi-locus sequence typing (MLST) of 63 strains for which both serotype and chemotype characterization was available. None of the three strain typing methods were correlative with each other, although for about 50% of the strains there was correlation between chemotype and genotype. To address this, we updated the methodology of GXM motif categorization for cryptococcal strains through analyzing filter-isolated EPS by 1D [1H] NMR and assigning GXM motifs along with the O-acetylation level. The result is a facile method using minimally processed EPS material coupled with simple cryptococcal strain classification by GXM motif expression. While this method increases the correlation between MLST genotype and GXM motif expression, further studies to establish the polysaccharide regulatory genes in cryptococcus will be necessary to understand the polysaccharide differences. In summary, none of the current classification methods correlated with each other, indicating a dissociation between genotype and phenotype, which poses a challenge to the cryptococcal field for explaining how phenotypic characteristics arise and are maintained.