Tackling microbial iron homeostasis: novel antimicrobial strategies.

The escalating threat of antimicrobial resistance demands innovative therapeutic strategies beyond classical targets. Recent insights into the mechanisms of bacterial iron acquisition - ranging from siderophores and heme uptake to ferrous iron transport - have enabled new approaches to impair pathogen growth and virulence. These pathways are increasingly being harnessed for therapeutic gain.

SARS-CoV-2 nucleocapsid induces hyperinflammation and vascular leakage through the Toll-like receptor signaling axis in macrophages.

Tens of thousands of severe COVID-19 cases are hospitalized weekly in the U.S., often driven by an imbalance between antiviral responses and inflammatory signaling, leading to uncontrolled cytokine secretion.

Predicting risk of cardiovascular events (PREVENT) score accuracy among people with HIV in the multicenter CNICS cohort.

Background: People with HIV (PWH) are at elevated cardiovascular risk, but existing calculators have suboptimal calibration for this population. The American Heart Association developed new prediction equations (PREVENT) to replace the pooled cohort equations (PCE). PREVENT has not been validated among PWH.

Distinct roles for NF-κB in hematopoietic stem cells and the bone marrow milieu in promoting hematopoietic aging.

Hematopoietic aging is characterized by chronic inflammation associated with myeloid bias, hematopoietic stem cell (HSC) accumulation, and functional HSC impairment. Yet it remains unclear how inflammation promotes aging phenotypes. Nuclear factor κB (NF-κB) both responds to and directs inflammation, and we present an experimental model of elevated NF-κB activity ("inhibitor of κB deficient" [IκB]) to dissect its role in hematopoietic aging phenotypes.

A computational workflow for assessing drug effects on temporal signaling dynamics reveals robustness in stimulus-specific NFκB signaling.

Single-cell studies of signal transduction have revealed complex temporal dynamics that determine downstream biological function. For example, the stimulus-specific dynamics of the transcription factor NFκB specify stimulus-specific gene expression programs, and loss of specificity leads to disease. Thus, it is intriguing to consider drugs that may restore signaling specificity in disease contexts, or reduce activity but maintain signaling specificity to avoid unwanted side effects.

Systems biology-enabled targeting of NF-κΒ and BCL2 overcomes microenvironment-mediated BH3-mimetic resistance in DLBCL.

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.

Gene regulatory logic of the interferon-β enhancer is characterized by two selectively deployed modes of transcription factor synergy.

Type I interferon IFNβ is a key immune response cytokine, and when its expression is dysregulated, it causes disease. The regulation of IFNβ enhancer has been a touchpoint of mammalian gene control research since the discovery of functional synergy between two stimulus-responsive transcription factors (TFs), nuclear factor kappa B (NFκB) and interferon regulatory factors (IRF). However, subsequent gene knockout studies revealed that in some conditions either NFκB or IRF activation can be dispensable, leaving the precise regulatory logic of IFNβ transcription an open question.

Phased epigenetic fragility and stability accelerate the genetic evolution of B-cells.

Unlabelled: Non-genetic heterogeneity can provide population robustness when responding to threats or making developmental decisions, but when the biological process rests on specific individuals (tissue-resident macrophages or genetic evolution), non-genetic heterogeneity degrades performance. Vaccine responses depend on the Darwinian evolution of B-cells to generate high-affinity, genetically-encoded antibodies, yet B-cell decision-making is non-genetically variable. In fact, B-cell epigenetic states are fragile during selection but stable during the proliferation burst.

IFNγ-induced memory in human macrophages is not sustained by epigenetic changes but the durability of the cytokine itself.

Macrophages, as key sentinel cells of the innate immune system, can retain memory of prior stimulus exposure. Interferon gamma (IFNγ) plays a central role in maintaining trained immunity and can induce potent memory in macrophages. Such memory is associated with the formation of enhancers that alter gene expression responses to subsequent stimuli.

Modeling heterogeneous signaling dynamics of macrophages reveals principles of information transmission in stimulus responses.

Macrophages initiate pathogen-appropriate immune responses with the activation dynamics of transcription factor NFκB mediating specificity. Live-cell imaging revealed the stimulus-response specificity of NFκB dynamics among populations of heterogeneous cells. To study stimulus-response specificity beyond what is experimentally accessible, we develop mathematical model simulations that capture the heterogeneity of stimulus-responsive NFκB dynamics and the stimulus-response specificity performance of the population.

Tensor-Based Integration of Time-Series Measurements Reveals Relationships Between Underlying Disease, Early Injury, and CD4+ Polarization in Liver Transplantation.

For patients with end-stage liver failure, liver transplantation (LT) remains the standard-of-care, though five-year allograft survival rates remain below 80%. Liver ischemia reperfusion injuries (LIRI) arise during transplant and contribute to allograft dysfunction. While many drivers of LIRI have been well-characterized, the relationships between LIRI and later immunological signatures remain poorly understood, possibly because of limited integrated studies examining immunological signatures across the LT process.

Synergy and antagonism in the integration of BCR and CD40 signals that control B-cell population expansion.

In response to infection or vaccination, lymph nodes must select antigen-reactive B-cells while eliminating auto-reactive B-cells. B-cells are instructed via B-cell receptor (BCR), which binds antigen, and CD40 receptor by antigen-recognizing T-cells. How BCR and CD40 signaling are integrated quantitatively to jointly determine B-cell fate decisions remains unclear.

Protocol for the imputation of stimulus-induced single-cell gene expression trajectories from time-series scRNA-seq data.

Single-cell RNA sequencing (scRNA-seq) measures cell-to-cell heterogeneous mRNA abundance but destroys the cell and precludes tracking of heterogeneous gene expression trajectories. Here, we present an approach to impute single-cell gene expression trajectories (scGETs) from time-series scRNA-seq measurements. We describe four main computational steps: dimensionality reduction, calculation of transition probability matrices, spline interpolation, and deconvolution to scGETs.

Macrophages maintain signaling fidelity in response to ligand mixtures.

Unlabelled: As immune sentinel cells, macrophages are required to respond specifically to diverse immune threats and initiate appropriate immune responses. This stimulus-response specificity (SRS) is in part encoded in the signaling dynamics of the NFκB transcription factor. While experimental stimulus-response studies have typically focused on single defined ligands, in physiological contexts cells are exposed to multi-ligand mixtures.

A computational workflow for assessing drug effects on temporal signaling dynamics reveals robustness in stimulus-specific NFκB signaling.

Single-cell studies of signal transduction have revealed complex temporal dynamics that determine downstream biological function. For example, the stimulus-specific dynamics of the transcription factor NFκB specify stimulus-specific gene expression programs, and loss of specificity leads to disease. Thus, it is intriguing to consider drugs that may restore signaling specificity in disease contexts, or reduce activity but maintain signaling specificity to avoid unwanted side effects.

Multicenter study of heart failure phenotypes and physician-adjudicated causes in people with HIV.

Background: Limited systematic data exist on heart failure phenotypes in contemporary HIV care, and no prior multicenter studies have investigated physician-adjudicated phenotypes and causes of heart failure in people with HIV (PWH).

Methods: We adjudicated heart failure events and sub-phenotypes occurring between January 1, 2010, and December 31, 2021, at two large urban clinical centers within the CFAR Network of Integrated Clinical Systems (CNICS) cohort. Using Cox proportional hazard regression, hazard ratios were calculated to examine associations of HIV-specific and cardiometabolic risk factors with incident heart failure among PWH.

[Etiology of osteonecrosis and bone marrow edema].

Background: The frequent use of magnetic resonance imaging (MRI) introduced "bone marrow edema" (BME) as a descriptive radiological term for hyperintense signal changes in fluid-sensitive sequences. With the optimization of MRI soft tissue contrast, BME has evolved into a valid prognostic indicator associated with pain genesis, trauma, mechanical overload, and progressive cartilage and joint destruction.

Diagnostics: Both osteonecrosis and BME manifest in early MRI as intraosseous fluid accumulation, characterized by hyperintense signals in T2-weighted and STIR sequences.

Temporal dose inversion properties of adaptive biomolecular circuits.

Cells have the capacity to encode and decode information in the temporal features of molecular signals. Many pathways, for example, generate either sustained or pulsatile responses depending on the context, and such diverse temporal behaviors have a profound impact on cell fate. Here we focus on how molecular pathways can convert the temporal features of dynamic signals, in particular how they can convert transient signals into persistent downstream events and vice versa.

Gene regulatory logic of the interferon-β enhancer contains multiple selectively deployed modes of transcription factor synergy.

Type I interferon IFNβ is a key regulator of the immune response, and its dysregulated expression causes disease. The regulation of IFNβ promoter activity has been a touchpoint of mammalian gene control research since the discovery of functional synergy between two stimulus-responsive transcription factors (TFs) nuclear factor kappa B (NFκB) and interferon regulatory factors (IRF). However, subsequent gene knockout studies revealed that this synergy is condition-dependent such that either NFκB or IRF activation can be dispensable, leaving the precise regulatory logic of IFNβ transcription an open question.

Macrophage memory emerges from coordinated transcription factor and chromatin dynamics.

Cells of the immune system operate in dynamic microenvironments where the timing, concentration, and order of signaling molecules constantly change. Despite this complexity, immune cells manage to communicate accurately and control inflammation and infection. It is unclear how these dynamic signals are encoded and decoded and if individual cells retain the memory of past exposure to inflammatory molecules.

NF-κB RelB suppresses the inflammatory gene expression programs of dendritic cells by competing with RelA for binding to target gene promoters.

A group of autoinflammatory disorders termed relopathies arise as a consequence of NF-κB dysregulation. Genetic loss of the NF-κB subunit RelB in humans and mice leads to autoimmunity and lethal multi-organ inflammatory pathology. Our recent study showed that this inflammatory pathology is independent of type I interferon signaling, and further identified dysregulation of a set of pro-inflammatory NF-κB target genes.

The golden goal of entatic state model design: lowering the internal reorganization energy leads to exponential increase in electron transfer rate.

We report a novel guanidine quinolinyl entatic state model system with an electron transfer rate on the order of 10 M s and remarkably little internal reorganization. Comparison between this system and previously reported TMGqu systems reveals an exponential correlation between the internal reorganization energy and the electron transfer rate.

Enhancing FAIRdata by providing digital workflows from data generation to the publication of data: an open source approach described for cyclic voltammetry.

Analytical data in chemistry and other disciplines is usually generated in different formats and lacks common data and metadata standards that are necessary for a FAIR handling of research data. In the work presented herein, we describe a workflow that uses non-standardized, in some cases proprietary, data formats from cyclic voltammetry measurements coming from individual devices as an instructive example, to yield open, standardized data that are annotated with rich metadata. The presented workflow includes concepts, software and infrastructure that can be used to support the whole data life cycle from the measurement of data to the publication of data and metadata in repositories.

Distinct causes of three phenotypic hallmarks of hematopoietic aging.

Hematopoietic aging is characterized by chronic inflammation associated with myeloid bias, HSC accumulation, and functional HSC impairment. Yet it remains unclear how inflammation promotes these aging phenotypes. NFkappaB both responds to and directs inflammation, and we present an experimental model of elevated NFkappaB activity (IkappaBminus) to dissect its role in hematopoietic aging phenotypes.

Linking Research Data with Physically Preserved Research Materials in Chemistry.

Results of scientific work in chemistry can usually be obtained in the form of materials and data. A big step towards transparency and reproducibility of the scientific work can be gained if scientists publish their data in research data repositories in a FAIR manner. Nevertheless, in order to make chemistry a sustainable discipline, obtaining FAIR data is insufficient and a comprehensive concept that includes preservation of materials is needed.