J Chem Phys. 2024 Dec 21;161(23):234107. doi: 10.1063/5.0227527.

ABSTRACT

We show that the resolution-dependent loss of bimolecular reactions in spatiotemporal Reaction-Diffusion Master Equations (RDMEs) is in agreement with the mean-field Collins-Kimball (C-K) theory of diffusion-limited reaction kinetics. The RDME is a spatial generalization of the chemical master equation, which enables studying stochastic reaction dynamics in spatially heterogeneous systems. It uses a regular Cartesian grid to partition space into locally well-mixed reaction compartments and treats diffusion as a jump reaction between neighboring grid cells. As the chance for reactants to be in the same grid cell decreases for smaller cell widths, the RDME loses bimolecular reactions in finer grids. We show that for a single homo-bimolecular reaction, the mesh spacing can be interpreted as the reaction radius of a well-mixed C-K rate. Then, the bimolecular reaction loss is consistent with diffusion-limited kinetics in the mean-field steady state. In this interpretation, the constant in a bimolecular reaction propensity is no longer the macroscopic reaction rate but the rate of the ballistic C-K step. For the same grid resolution, different diffusion models in RDME, such as those based on finite differences and Gaussian jumps, represent different reaction radii.

PMID:39679507 | DOI:10.1063/5.0227527

Curr Zool. 2024 Mar 11;70(6):765-779. doi: 10.1093/cz/zoae009. eCollection 2024 Dec.

ABSTRACT

In social groups, competition for individual advantage is balanced with cooperation, for the collective benefit. Selection against aggression has favored cooperation and non-aggressive competitive strategies. Because social play is a behavioral system that fluctuates between cooperation and competition, selection against aggression might have especially influenced this behavior. African savannah elephants (Loxodonta africana) are a low aggressive species, therefore suitable to investigate this aspect. We collected all occurrences observational audio-video data on social play, aggression/threats, and affiliation on an African elephant colony housed in a 25-ha open space at Parque de la Naturaleza de Cabarceno (Cantabria, Spain) and composed of 4 family groups (3 immature males, 3 immature females, and 7 adult females) and 2 adult males. Anticipating the influence of reduced aggression, we found that social play decreased with age, persisting in adults, and that it was highest in males. Social play was associated with affiliation (informing cooperation). Indeed, individuals that were central in the social play network were also central in the affiliation network. For immature subjects, we found a correlation between social play and affiliation sociomatrices. However, such correlation was absent in adults and social play mostly occurred between families. Despite the limitations related to dealing with a small captive group, this study largely supports the idea that the features of social play in African savannah elephants may be related to low aggression. This investigation hints toward a non-purely cooperative use of play, possibly as a non-aggressive interaction that accommodates different levels of cooperation and competition.

PMID:39678814 | PMC:PMC11634687 | DOI:10.1093/cz/zoae009

iScience. 2024 May 30;27(6):110134. doi: 10.1016/j.isci.2024.110134. eCollection 2024 Jun 21.

ABSTRACT

Effective immune-cell responses depend on collective decision-making mediated by diffusible intercellular signaling proteins called cytokines. Here, we designed a three-dimensional spatiotemporal modeling framework and a precise finite-element simulation setup to systematically investigate the origin and consequences of spatially inhomogeneous cytokine distributions in lymph nodes. We found that such inhomogeneities are critical for effective paracrine signaling, and they do not arise by diffusion and uptake alone, but rather depend on properties of the cell population such as an all-or-none behavior of cytokine secreting cells. Furthermore, we assessed the regulatory properties of negative and positive feedback in combination with diffusion-limited signaling dynamics, and we derived statistical quantities to characterize the spatiotemporal signaling landscape in the context of specific tissue architectures. Overall, our simulations highlight the complex spatiotemporal dynamics imposed by cell-cell signaling with diffusible ligands, which entails a large potential for fine-tuned biological control especially if combined with feedback mechanisms.

PMID:39678490 | PMC:PMC11639737 | DOI:10.1016/j.isci.2024.110134

Front Genet. 2024 Nov 29;15:1460351. doi: 10.3389/fgene.2024.1460351. eCollection 2024.

ABSTRACT

INTRODUCTION: The agriculture genomics community has numerous data submission standards available, but the standards for describing and storing single-cell (SC, e.g., scRNA- seq) data are comparatively underdeveloped.

METHODS: To bridge this gap, we leveraged recent advancements in human genomics infrastructure, such as the integration of the Human Cell Atlas Data Portal with Terra, a secure, scalable, open-source platform for biomedical researchers to access data, run analysis tools, and collaborate. In parallel, the Single Cell Expression Atlas at EMBL-EBI offers a comprehensive data ingestion portal for high-throughput sequencing datasets, including plants, protists, and animals (including humans). Developing data tools connecting these resources would offer significant advantages to the agricultural genomics community. The FAANG data portal at EMBL-EBI emphasizes delivering rich metadata and highly accurate and reliable annotation of farmed animals but is not computationally linked to either of these resources.

RESULTS: Herein, we describe a pilot-scale project that determines whether the current FAANG metadata standards for livestock can be used to ingest scRNA-seq datasets into Terra in a manner consistent with HCA Data Portal standards. Importantly, rich scRNA-seq metadata can now be brokered through the FAANG data portal using a semi-automated process, thereby avoiding the need for substantial expert curation. We have further extended the functionality of this tool so that validated and ingested SC files within the HCA Data Portal are transferred to Terra for further analysis. In addition, we verified data ingestion into Terra, hosted on Azure, and demonstrated the use of a workflow to analyze the first ingested porcine scRNA-seq dataset. Additionally, we have also developed prototype tools to visualize the output of scRNA-seq analyses on genome browsers to compare gene expression patterns across tissues and cell populations. This JBrowse tool now features distinct tracks, showcasing PBMC scRNA-seq alongside two bulk RNA-seq experiments.

DISCUSSION: We intend to further build upon these existing tools to construct a scientist-friendly data resource and analytical ecosystem based on Findable, Accessible, Interoperable, and Reusable (FAIR) SC principles to facilitate SC-level genomic analysis through data ingestion, storage, retrieval, re-use, visualization, and comparative annotation across agricultural species.

PMID:39678381 | PMC:PMC11638175 | DOI:10.3389/fgene.2024.1460351

bioRxiv [Preprint]. 2024 Dec 5:2024.11.30.626166. doi: 10.1101/2024.11.30.626166.

ABSTRACT

In Diffuse Large B-cell Lymphoma (DLBCL), elevated anti-apoptotic BCL2-family proteins (e.g., MCL1, BCL2, BCLXL) and NF-κB subunits (RelA, RelB, cRel) confer poor prognosis. Heterogeneous expression, regulatory complexity, and redundancy offsetting the inhibition of individual proteins, complicate the assignment of targeted therapy. We combined flow cytometry 'fingerprinting', immunofluorescence imaging, and computational modeling to identify therapeutic vulnerabilities in DLBCL. The combined workflow predicted selective responses to BCL2 inhibition (venetoclax) and non-canonical NF-κB inhibition (Amgen16). Within the U2932 cell line we identified distinct resistance mechanisms to BCL2 inhibition in cellular sub-populations recapitulating intratumoral heterogeneity. Co-cultures with CD40L-expressing stromal cells, mimicking the tumor microenvironment (TME), induced resistance to BCL2 and BCLXL targeting BH3-mimetics via cell-type specific upregulation of BCLXL or MCL1. Computational models, validated experimentally, showed that basal NF-κB activation determined whether CD40 activation drove BH3-mimetic resistance through upregulation of RelB and BCLXL, or cRel and MCL1. High basal NF-κB activity could be overcome by inhibiting BTK to resensitize cells to BH3-mimetics in CD40L co-culture. Importantly, non-canonical NF-κB inhibition overcame heterogeneous compensatory BCL2 upregulation, restoring sensitivity to both BCL2-and BCLXL-targeting BH3-mimetics. Combined molecular fingerprinting and computational modelling provides a strategy for the precision use of BH3-mimetics and NF-κB inhibitors in DLBCL.

KEY POINTS: TME-mimicking co-culture provides resistance to BH3-mimetics through BCLXL, which can be overcome by inhibition of non-canonical NF-κB.Multidisciplinary profiling reveals how high NF-κB activity leads to crosstalk, and BH3-mimetic resistance counteracted by BTK inhibition.

PMID:39677808 | PMC:PMC11642794 | DOI:10.1101/2024.11.30.626166

bioRxiv [Preprint]. 2024 Dec 6:2024.12.04.626850. doi: 10.1101/2024.12.04.626850.

ABSTRACT

The original 100.3 Mb reference genome for Caenorhabditis elegans , generated from the wild-type laboratory strain N2, has been crucial for analysis of C. elegans since 1998 and has been considered complete since 2005. Unexpectedly, this long-standing reference was shown to be incomplete in 2019 by a genome assembly from the N2-derived strain VC2010. Moreover, genetically divergent versions of N2 have arisen over decades of research and hindered reproducibility of C. elegans genetics and genomics. Here we provide a 106.4 Mb gap-free, telomere-to-telomere genome assembly of C. elegans , generated from CGC1, an isogenic derivative of the N2 strain. We used improved long-read sequencing and manual assembly of 43 recalcitrant genomic regions to overcome deficiencies of prior N2 and VC2010 assemblies, and to assemble tandem repeat loci including a 772-kb sequence for the 45S rRNA genes. While many differences from earlier assemblies came from repeat regions, unique additions to the genome were also found. Of 19,972 protein-coding genes in the N2 assembly, 19,790 (99.1%) encode products that are unchanged in the CGC1 assembly. The CGC1 assembly also may encode 183 new protein-coding and 163 new ncRNA genes. CGC1 thus provides both a completely defined reference genome and corresponding isogenic wild-type strain for C. elegans , allowing unique opportunities for model and systems biology.

PMID:39677790 | PMC:PMC11643116 | DOI:10.1101/2024.12.04.626850

bioRxiv [Preprint]. 2024 Dec 4:2024.12.03.626567. doi: 10.1101/2024.12.03.626567.

ABSTRACT

Many organisms maintain generalized stress responses activated by adverse conditions. Although details vary, a common theme is the redirection of transcriptional and translational capacity away from growth-promoting genes and toward defense genes. Yet the precise roles of these coupled programs are difficult to dissect. Here we investigated Saccharomyces cerevisiae responding to salt as a model stressor. We used molecular, genomic, and single-cell microfluidic methods to examine the interplay between transcription factors Msn2 and Msn4 that induce stress-defense genes and Dot6 and Tod6 that transiently repress growth-promoting genes during stress. Surprisingly, loss of Dot6/Tod6 led to slower acclimation to salt, whereas loss of Msn2/4 produced faster growth during stress. This supports a model where transient repression of growth-promoting genes accelerates the Msn2/4 response, which is essential for acquisition of subsequent peroxide tolerance. Remarkably, we find that Msn2/4 regulate DOT6 mRNA production, influence Dot6 activation dynamics, and are required for full repression of growth-promoting genes. Thus, Msn2/4 directly regulate resource reallocation needed to mount their own response. We discuss broader implications for common stress responses across organisms.

SYNOPSIS: This study investigates how genes induced and repressed in the yeast Environmental Stress Response contribute to stress tolerance, growth rate, and resource allocation. The work uses molecular, genomic, and systems biology approaches to present new insights into eukaryotic responses to acute stress.

HIGHLIGHTS: Cells lacking stress-activated transcription factors have a faster post-stress growth rateCells lacking repressors of growth-promoting genes have a slower post-stress growth rateStress-defense factors control the induction of growth-promoting gene repressors, thereby coordinating the resource re-allocation needed for the response.

PMID:39677602 | PMC:PMC11642900 | DOI:10.1101/2024.12.03.626567

Evol Lett. 2024 Jul 22;8(6):841-850. doi: 10.1093/evlett/qrae037. eCollection 2024 Dec.

ABSTRACT

Attractiveness is not solely determined by a single sexual trait but rather by a combination of traits. Because the response of the chooser is based on the combination of sexual traits in the courter, variation in the chooser's responses that are attributable to the opposite-sex courter genotypes (i.e., the indirect genetic effects [IGEs] on chooser response) can reflect genetic variation in overall attractiveness. This genetic variation can be associated with the genetic basis of other traits in both the chooser and the courter. Investigating this complex genetic architecture, including IGEs, can enhance our understanding of the evolution of mate choice. In the present study on the field cricket Gryllus bimaculatus, we estimated (1) genetic variation in overall attractiveness and (2) genetic correlations between overall attractiveness and other pre- and postcopulatory traits (e.g., male latency to sing, female latency to mount, male guarding intensity, male and female body mass, male mandible size, and testis size) within and between sexes. We revealed a genetic basis for attractiveness in both males and females. Furthermore, a genetic variance associated with female attractiveness was correlated with a genetic variance underlying larger male testes. Our findings imply that males that mate with attractive females can produce offspring that are successful in terms of precopulatory sexual selection (daughters who are attractive) and postcopulatory sexual selection (sons with an advantage in sperm competition), potentially leading to runaway sexual selection. Our study exemplifies how the incorporation of the IGE framework provides novel insights into the evolution of mate choice.

PMID:39677572 | PMC:PMC11637604 | DOI:10.1093/evlett/qrae037

PNAS Nexus. 2024 Nov 20;3(12):pgae521. doi: 10.1093/pnasnexus/pgae521. eCollection 2024 Dec.

ABSTRACT

To overcome their limited genetic capacity, numerous viruses encode multifunctional proteins. The birnavirus VP3 protein plays key roles during infection, including scaffolding of the viral capsid during morphogenesis, recruitment, and regulation of the viral RNA polymerase, shielding of the double-stranded RNA genome and targeting of host endosomes for genome replication, and immune evasion. The dimeric form of VP3 is critical for these functions. In previous work, we determined the X-ray structure of the central domains (D2-D3) of VP3 from the infectious bursal disease virus (IBDV). However, the structure and function of the IBDV VP3 N-terminal domain (D1) could not be determined at that time. Using integrated structural biology approaches and functional cell assays, here we characterize the IBDV VP3 D1 domain, unveiling its unexplored roles in virion stability and infection. The X-ray structure of D1 shows that this domain folds in four α-helices arranged in parallel dimers, which are essential for maintaining the dimeric arrangement of the full-length protein. Combining small-angle X-ray scattering analyses with molecular dynamics simulations allowed us to build a structural model for the D1-D3 domains. This model consists of an elongated structure with high flexibility in the D2-D3 connection, keeping D1 as the only driver of VP3 dimerization. Using reverse genetics tools, we show that the obliteration of D1 domain prevents the VP3 scaffold function during capsid assembly and severely impacts IBDV infection. Altogether, our study elucidates the structure of the VP3 D1 domain and reveals its role in VP3 protein dimerization and IBDV infection.

PMID:39677362 | PMC:PMC11645250 | DOI:10.1093/pnasnexus/pgae521

Front Cell Dev Biol. 2024 Nov 29;12:1498346. doi: 10.3389/fcell.2024.1498346. eCollection 2024.

ABSTRACT

Early embryonic development is a complex process where undifferentiated cells lose their pluripotency and start to gastrulate. During gastrulation, three germ layers form, giving rise to different cell lineages and organs. This process is regulated by transcription factors and epigenetic regulators, including non-canonical polycomb repressive complex 1s (ncPRC1s). Previously, we reported that ncPRC1-member RYBP (RING1 and YY1 binding protein) is crucial for embryonic implantation and cardiac lineage commitment in mice. However, the role of RYBP in gastrulation and mesoderm formation has not yet been defined. In this study, we used 2D and 3D in vitro model systems, to analyze the role of RYBP in mesoderm formation. First, we showed that cardiac and endothelial progenitors-both derived from mesoderm-are underrepresented in the Rybp -/- cardiac colonies. In the absence of RYBP, the formation of major germ layers was also disrupted, and the expression of mesoderm- (Brachyury, Eomes, and Gsc) and endoderm-specific (Sox17, Gata4) genes was significantly downregulated. Using 3D embryoid bodies as gastrulation models, we showed that RYBP can co-localize with mesoderm lineage marker protein BRACHYURY and endoderm marker protein GATA4 and both proteins. In mutants, both proteins were detected at low levels and showed altered distribution. Additionally, we compared our in vitro results to available in vivo single-cell transcriptomes and showed that Rybp and Brachyury co-expressed in the primitive streak and six mesodermal clusters. Since caudal mesoderm exhibited one of the strongest co-expressions, we tested axial elongation in wt and Rybp -/- gastruloids. In the absence of RYBP, gastruloids exhibited shortened tails and low BRACHYURY levels in the tailbud. Finally, we identified BRACHYURY as a novel binding partner of RYBP and presented evidence of possible cooperative function during mesoderm formation and axial elongation. Together, our results demonstrate the previously unknown role of RYBP in mesoderm formation. We believe our findings will contribute to better understanding of the highly conserved process of gastrulation.

PMID:39676794 | PMC:PMC11638158 | DOI:10.3389/fcell.2024.1498346

Small. 2024 Dec 15:e2408871. doi: 10.1002/smll.202408871. Online ahead of print.

ABSTRACT

Extracellular vesicles (EVs) play a crucial role in the occurrence and progression of cancer. The efficient isolation and analysis of EVs for early cancer diagnosis and prognosis have gained significant attention. In this study, for the first time, a rapid and visually detectable method termed freeze-thaw-induced floating patterns of gold nanoparticles (FTFPA) is proposed, which surpasses current state-of-the-art technologies by achieving a 100 fold improvement in the limit of detection of EVs. Notably, it allows for multi-dimensional visualizations of EVs through site-specific oligonucleotide incorporation. This capability empowers FTFPA to accurately identify EVs derived from subtypes of breast cancers with artificial intelligence algorithms. Intriguingly, learning the freezing-thawing-microstructures of EVs with a random forest algorithm is not only able to distinguish their original cell lines (with an accuracy of 95.56%), but also succeed in processing clinical samples (n = 156) to identify EVs by their healthy donors, breast lump and breast cancer subtypes (Luminal A, Triple-negative breast cancer, and Luminal B) with an accuracy of 83.33%. Therefore, this AI-empowered micro-visualization method establishes a rapid and precise point-of-care platform that is applicable to both fundamental research and clinical settings.

PMID:39676518 | DOI:10.1002/smll.202408871

Metabolomics. 2024 Dec 15;21(1):9. doi: 10.1007/s11306-024-02199-8.

ABSTRACT

INTRODUCTION: Outside of case-control settings, ethnicity specific changes in the human metabolome are understudied especially in community dwelling, ageing men. Characterising serum for age and ethnicity specific features can enable tailored therapeutics research and improve our understanding of the interplay between age, ethnicity, and metabolism in global populations.

OBJECTIVE: A metabolomics approach was adopted to profile serum metabolomes in middle-aged and elderly men of different ethnicities from the Northwest of England, UK.

METHODS: Serum samples from 572 men of White European (WE), South Asian (SA), and African-Caribbean (AC) ethnicities, ranging between 40 and 86 years were analysed. A combination of liquid chromatography (LC) and gas chromatography (GC) coupled to high-resolution mass spectrometry (MS) was used to generate the metabolomic profiles. Partial Least Squares Discriminant Analysis (PLS-DA) based classification models were built and validated using resampling via bootstrap analysis and permutation testing. Features were putatively annotated using public Human Metabolome Database (HMDB) and Golm Metabolite Database (GMD). Variable Importance in Projection (VIP) scores were used to determine features of interest, after which pathway enrichment analysis was performed.

RESULTS: Using profiles from our analysis we classify subjects by their ethnicity with an average correct classification rate (CCR) of 90.53% (LC-MS data) and 85.58% (GC-MS data). Similar classification by age (< 60 vs. ≥ 60 years) returned CCRs of 90.20% (LC-MS) and 71.13% (GC-MS). VIP scores driven feature selection revealed important compounds from putatively annotated lipids (subclasses including fatty acids and carboxylic acids, glycerophospholipids, steroids), organic acids, amino acid derivatives as key contributors to the classifications. Pathway enrichment analysis using these features revealed statistically significant perturbations in energy metabolism (TCA cycle), N-Glycan and unsaturated fatty acid biosynthesis linked pathways amongst others.

CONCLUSION: We report metabolic differences measured in serum that can be attributed to ethnicity and age in healthy population. These results strongly emphasise the need to consider confounding effects of inherent metabolic variations driven by ethnicity of participants in population-based metabolic profiling studies. Interpretation of energy metabolism, N-Glycan and fatty acid biosynthesis should be carefully decoupled from the underlying differences in ethnicity of participants.

PMID:39676138 | DOI:10.1007/s11306-024-02199-8

Plant Cell Rep. 2024 Dec 15;44(1):6. doi: 10.1007/s00299-024-03398-2.

ABSTRACT

A novel fluorescent i-motif DNA silver nanoclusters system has been developed for visualization of reactive oxygen species in plants, enabling the detection of intracellular signaling in plant cells. Reactive oxygen species (ROS) are crucial in plant growth, defense, and stress responses, making them vital for improving crop resilience. Various ROS sensing methods for plants have been developed to detect ROS in vitro and in vivo. However, each method comes its own advantages and disadvantages, leading to an increasing demand for a simple and effective sensory system for ROS detection in plants. Here, we introduce novel DNA silver nanoclusters (DNA/AgNCs) sensors for visualizing ROS in plants. Two sensors, C20/AgNCs and FAM-C20/AgNCs-Cy5, detect intracellular ROS signaling in response to stimuli, such as abscisic acid, salicylic acid, ethylene, and bacterial peptide elicitor flg22. Notably, FAM-C20/AgNCs-Cy5 exceeds the sensing capabilities of HyPer7, a widely recognized ROS sensor. Taken together, we suggest that fluorescent i-motif DNA/AgNCs system is an effective tool for visualizing ROS signals in plant cells. This advancement is important to advancing our understanding of ROS-mediated processes in plant biology.

PMID:39676128 | DOI:10.1007/s00299-024-03398-2

Metabolomics. 2024 Dec 15;21(1):8. doi: 10.1007/s11306-024-02206-y.

ABSTRACT

INTRODUCTION: Rapid detection and identification of pathogens and antimicrobial susceptibility is essential for guiding appropriate antimicrobial therapy and reducing morbidity and mortality associated with sepsis.

OBJECTIVES: The metabolic response of clinical isolates of Klebsiella oxytoca exposed to different concentrations of ciprofloxacin (the second generation of quinolones antibiotics) were studied in order to investigate underlying mechanisms associated with antimicrobial resistance (AMR).

METHODS: Metabolomics investigations were performed using Fourier-transform infrared (FT-IR) spectroscopy as a metabolic fingerprinting approach combined with gas chromatography-mass spectrometry (GC-MS) for metabolic profiling.

RESULTS: Our findings demonstrated that metabolic fingerprints provided by FT-IR analysis allowed for the differentiation of susceptible and resistant isolates. GC-MS analysis validated these findings, while also providing a deeper understanding of the metabolic alterations caused by exposure to ciprofloxacin. GC-MS metabolic profiling detected 176 metabolic features in the cellular extracts cultivated on BHI broth, and of these, 137 could be identified to Metabolomics Standards Initiative Level 2. Data analysis showed that 40 metabolites (30 Level 2 and 10 unknown) were differentiated between susceptible and resistant isolates. The identified metabolites belonging to central carbon metabolism; arginine and proline metabolism; alanine, aspartate and glutamate metabolism; and pyruvate metabolism. Univariate receiver operating characteristic (ROC) curve analyses revealed that six of these metabolites (glycerol-3-phosphate, O-phosphoethanolamine, asparagine dehydrate, maleimide, tyrosine, and alanine) have a crucial role in distinguishing susceptible from resistant isolates (AUC > 0.84) and contributing to antimicrobial resistance in K. oxtytoca.

CONCLUSION: Our study provides invaluable new insights into the mechanisms underlying development of antimicrobial resistance in K. oxytoca suggests potential therapeutic targets for prevention and identification of AMR in K. oxytoca infections.

PMID:39676074 | DOI:10.1007/s11306-024-02206-y

J Biol Chem. 2024 Dec 13:108088. doi: 10.1016/j.jbc.2024.108088. Online ahead of print.

ABSTRACT

While ATP-site inhibitors for protein-tyrosine kinases are often effective drugs, their clinical utility can be limited by off-target activity and acquired resistance mutations due to the conserved nature of the ATP-binding site. However, combining ATP-site and allosteric kinase inhibitors can overcome these shortcomings in a double-drugging framework. Here we explored the allosteric effects of two pyrimidine diamines, PDA1 and PDA2, on the conformational dynamics and activity of the Src-family tyrosine kinase Hck, a promising drug target for acute myeloid leukemia. Using 1H-15N HSQC NMR, we mapped the binding site for both analogs to the SH3 domain. Despite the shared binding site, PDA1 and PDA2 had opposing effects on near-full-length Hck dynamics by hydrogen-deuterium exchange mass spectrometry, with PDA1 stabilizing and PDA2 disrupting the overall kinase conformation. Kinase activity assays were consistent with these observations, with PDA2 enhancing kinase activity while PDA1 was without effect. Molecular dynamics simulations predicted selective bridging of the kinase domain N-lobe and SH3 domain by PDA1, a mechanism of allosteric stabilization supported by site-directed mutagenesis of N-lobe contact sites. Cellular thermal shift assays confirmed SH3 domain-dependent interaction of PDA1 with wild-type Hck in myeloid leukemia cells and with a kinase domain gatekeeper mutant (T338M). These results identify PDA1 as a starting point for Src-family kinase allosteric inhibitor development that may work in concert with ATP-site inhibitors to suppress the evolution of resistance.

PMID:39675702 | DOI:10.1016/j.jbc.2024.108088

Prev Vet Med. 2024 Dec 13:106408. doi: 10.1016/j.prevetmed.2024.106408. Online ahead of print.

NO ABSTRACT

PMID:39674682 | DOI:10.1016/j.prevetmed.2024.106408

Lancet Planet Health. 2024 Dec;8(12):e1079-e1087. doi: 10.1016/S2542-5196(24)00238-9.

ABSTRACT

BACKGROUND: Aedes aegypti spread pathogens affecting humans, including dengue, Zika, and yellow fever viruses. Anthropogenic climate change is altering the spatial distribution of Ae aegypti and therefore the locations at risk of vector-borne disease. In addition to climate change, natural climate variability, resulting from internal atmospheric processes and interactions between climate system components (eg, atmosphere-land and atmosphere-ocean interactions), determines climate outcomes. However, the role of natural climate variability in modifying the effects of anthropogenic climate change on future environmental suitability for Ae aegypti has not been assessed fully. In this study, we aim to assess uncertainty arising from natural climate variability in projections of Ae aegypti suitability up to the year 2100.

METHODS: In this mathematical modelling study, we developed an ecological model in which Ae aegypti population dynamics depend on climate variables (temperature and rainfall). We used 100 projections of future climate from the Community Earth System Model, a comprehensive climate model that simulates natural climate variability as well as anthropogenic climate change, in combination with our ecological model to generate a range of equally plausible scenarios describing the global distribution of suitable conditions for Ae aegypti up to 2100. Each of these scenarios corresponds to a single climate projection, allowing us to explore the difference in Ae aegypti suitability between the most-suitable and the least-suitable projections.

FINDINGS: Our key finding was that natural climate variability generates substantial variation in future projections of environmental suitability for Ae aegypti. Even for projections generated under the same Shared Socioeconomic Pathway (SSP) scenario (SSP3-7.0), in 2100 climatic conditions in London might be suitable for Ae aegypti for 0-5 months of the year, depending on natural climate variability.

INTERPRETATION: Natural climate variability affects environmental suitability for important disease vectors. Some regions could experience vector-borne disease outbreaks earlier than expected under climate change alone.

FUNDING: Engineering and Physical Sciences Research Council and Wellcome Trust.

PMID:39674197 | DOI:10.1016/S2542-5196(24)00238-9

Artif Intell Med. 2024 Dec 11;160:103049. doi: 10.1016/j.artmed.2024.103049. Online ahead of print.

ABSTRACT

Multi-omics data have revolutionized biomedical research by providing a comprehensive understanding of biological systems and the molecular mechanisms of disease development. However, analyzing multi-omics data is challenging due to high dimensionality and limited sample sizes, necessitating proper data-reduction pipelines to ensure reliable analyses. Additionally, its multimodal nature requires effective data-integration pipelines. While several dimensionality reduction and data fusion algorithms have been proposed, crucial aspects are often overlooked. Specifically, the choice of projection space dimension is typically heuristic and uniformly applied across all omics, neglecting the unique high dimension small sample size challenges faced by individual omics. This paper introduces a novel multi-modal dimensionality reduction pipeline tailored to individual views. By leveraging intrinsic dimensionality estimators, we assess the curse-of-dimensionality impact on each view and propose a two-step reduction strategy for significantly affected views, combining feature selection with feature extraction. Compared to traditional uniform reduction pipelines in a crucial and supervised multi-omics analysis setting, our approach shows significant improvement. Additionally, we explore three effective unsupervised multi-omics data fusion methods rooted in the main data fusion strategies to gain insights into their performance under crucial, yet overlooked, settings.

PMID:39673960 | DOI:10.1016/j.artmed.2024.103049

Nucleic Acids Res. 2024 Dec 14:gkae1203. doi: 10.1093/nar/gkae1203. Online ahead of print.

ABSTRACT

Gene expression is a multi-step process that converts DNA-encoded information into proteins, involving RNA transcription, maturation, degradation, and translation. While transcriptional control is a major regulator of protein levels, the role of post-transcriptional processes such as RNA processing and degradation is less well understood due to the challenge of measuring their contributions individually. To address this challenge, we investigated the control of gene expression in Trypanosoma brucei, a unicellular parasite assumed to lack transcriptional control. Instead, mRNA levels in T. brucei are controlled by post-transcriptional processes, which enabled us to disentangle the contribution of both processes to total mRNA levels. In this study, we developed an efficient metabolic RNA labeling approach and combined ultra-short metabolic labeling with transient transcriptome sequencing (TT-seq) to confirm the long-standing assumption that RNA polymerase II transcription is unregulated in T. brucei. In addition, we established thiol (SH)-linked alkylation for metabolic sequencing of RNA (SLAM-seq) to globally quantify RNA processing rates and half-lives. Our data, combined with scRNA-seq data, indicate that RNA processing and stability independently affect total mRNA levels and contribute to the variability seen between individual cells in African trypanosomes.

PMID:39673807 | DOI:10.1093/nar/gkae1203

Nucleic Acids Res. 2024 Dec 14:gkae1200. doi: 10.1093/nar/gkae1200. Online ahead of print.

ABSTRACT

Streptococcus pyogenes, or Group A Streptococcus (GAS), is a commensal bacteria and human pathogen. Central to GAS pathogenesis is the presence of prophage encoded virulence genes. The conserved phage gene for the protein paratox (Prx) is genetically linked to virulence genes, but the reason for this linkage is unknown. Prx inhibits GAS quorum sensing and natural competence by binding the transcription factor ComR. However, inhibiting ComR does not explain the virulence gene linkage. To address this, we took a mass spectrometry approach to search for other Prx interaction partners. The data demonstrates that Prx binds numerous DNA-binding proteins and transcriptional regulators. We show binding of Prx in vitro with the GAS protein Esub1 (SpyM3_0890) and the phage protein JM3 (SpyM3_1246). An Esub1:Prx complex X-ray crystal structure reveals that Esub1 and ComR possess a conserved Prx-binding helix. Computational modelling predicts that the Prx-binding helix is present in several, but not all, binding partners. Namely, JM3 lacks the Prx-binding helix. As Prx is conformationally dynamic, this suggests partner-dependent binding modes. Overall, Prx acts as a metabolic regulator of GAS to maintain the phage genome. As such, Prx maybe a direct contributor to the pathogenic conversion of GAS.

PMID:39673798 | DOI:10.1093/nar/gkae1200