Fatty acid synthase (FASN) is a tumor-cell-intrinsic metabolic checkpoint restricting T-cell immunity.

Fatty acid synthase (FASN)-catalyzed endogenous lipogenesis is a hallmark of cancer metabolism. However, whether FASN is an intrinsic mechanism of tumor cell defense against T cell immunity remains unexplored. To test this hypothesis, here we combined bioinformatic analysis of the FASN-related immune cell landscape, real-time assessment of cell-based immunotherapy efficacy in CRISPR/Cas9-based FASN gene knockout (FASN KO) cell models, and mathematical and mechanistic evaluation of FASN-driven immunoresistance.

Computational modeling of angiogenesis: The importance of cell rearrangements during vascular growth.

Angiogenesis is the process wherein endothelial cells (ECs) form sprouts that elongate from the pre-existing vasculature to create new vascular networks. In addition to its essential role in normal development, angiogenesis plays a vital role in pathologies such as cancer, diabetes and atherosclerosis. Mathematical and computational modeling has contributed to unraveling its complexity.

Membrane rigidity regulates E. coli proliferation rates.

Combining single cell experiments, population dynamics and theoretical methods of membrane mechanics, we put forward that the rate of cell proliferation in E. coli colonies can be regulated by modifiers of the mechanical properties of the bacterial membrane. Bacterial proliferation was modelled as mediated by cell division through a membrane constriction divisome based on FtsZ, a mechanically competent protein at elastic interaction against membrane rigidity.

Pitting of malaria parasites in microfluidic devices mimicking spleen interendothelial slits.

The spleen is a hematopoietic organ that participates in cellular and humoral immunity. It also serves as a quality control mechanism for removing senescent and/or poorly deformable red blood cells (RBCs) from circulation. Pitting is a specialized process by which the spleen extracts particles, including malaria parasites, from within circulating RBCs during their passage through the interendothelial slits (IES) in the splenic cords.

Blood Rheological Characterization of β-Thalassemia Trait and Iron Deficiency Anemia Using Front Microrheometry.

The purpose of this work is to develop a hematocrit-independent method for the detection of beta-thalassemia trait (β-TT) and iron deficiency anemia (IDA), through the rheological characterization of whole blood samples from different donors. The results obtained herein are the basis for the development of a front microrheometry point-of-care device for the diagnosis and clinical follow-up of β-TT patients suffering hematological diseases and alterations in the morphology of the red blood cell (RBC). The viscosity is calculated as a function of the mean front velocity by detecting the sample fluid-air interface advancing through a microfluidic channel.

Microrheometer for Biofluidic Analysis: Electronic Detection of the Fluid-Front Advancement.

The motivation for this study was to develop a microdevice for the precise rheological characterization of biofluids, especially blood. The method presented was based on the principles of rheometry and fluid mechanics at the microscale. Traditional rheometers require a considerable amount of space, are expensive, and require a large volume of sample.

Bivalent chromatin as a therapeutic target in cancer: An in silico predictive approach for combining epigenetic drugs.

Tumour cell heterogeneity is a major barrier for efficient design of targeted anti-cancer therapies. A diverse distribution of phenotypically distinct tumour-cell subpopulations prior to drug treatment predisposes to non-uniform responses, leading to the elimination of sensitive cancer cells whilst leaving resistant subpopulations unharmed. Few strategies have been proposed for quantifying the variability associated to individual cancer-cell heterogeneity and minimizing its undesirable impact on clinical outcomes.

A multiscale model of complex endothelial cell dynamics in early angiogenesis.

We introduce a hybrid two-dimensional multiscale model of angiogenesis, the process by which endothelial cells (ECs) migrate from a pre-existing vascular bed in response to local environmental cues and cell-cell interactions, to create a new vascular network. Recent experimental studies have highlighted a central role of cell rearrangements in the formation of angiogenic networks. Our model accounts for this phenomenon via the heterogeneous response of ECs to their microenvironment.

Abnormal morphology biases hematocrit distribution in tumor vasculature and contributes to heterogeneity in tissue oxygenation.

Oxygen heterogeneity in solid tumors is recognized as a limiting factor for therapeutic efficacy. This heterogeneity arises from the abnormal vascular structure of the tumor, but the precise mechanisms linking abnormal structure and compromised oxygen transport are only partially understood. In this paper, we investigate the role that red blood cell (RBC) transport plays in establishing oxygen heterogeneity in tumor tissue.

An Integrated Detection Method for Flow Viscosity Measurements in Microdevices.

Point-of-care devices can analyze or characterize a sample in a short time. New technologies in medical science seek integrations of different measurement techniques for a complete analysis. This study describes the fabrication method, tests, and results of microtechnology as an approach for an integrated rheometer.

Tumor Cell-Intrinsic Immunometabolism and Precision Nutrition in Cancer Immunotherapy.

One of the greatest challenges in the cancer immunotherapy field is the need to biologically rationalize and broaden the clinical utility of immune checkpoint inhibitors (ICIs). The balance between metabolism and immune response has critical implications for overcoming the major weaknesses of ICIs, including their lack of universality and durability. The last decade has seen tremendous advances in understanding how the immune system's ability to kill tumor cells requires the conspicuous metabolic specialization of T-cells.

The LSD1 inhibitor iadademstat (ORY-1001) targets SOX2-driven breast cancer stem cells: a potential epigenetic therapy in luminal-B and HER2-positive breast cancer subtypes.

SOX2 is a core pluripotency-associated transcription factor causally related to cancer initiation, aggressiveness, and drug resistance by driving the self-renewal and seeding capacity of cancer stem cells (CSC). Here, we tested the ability of the clinically proven inhibitor of the lysine-specific demethylase 1 (LSD1/KDM1A) iadademstat (ORY-100) to target SOX2-driven CSC in breast cancer. Iadademstat blocked CSC-driven mammosphere formation in breast cancer cell lines that are dependent on SOX2 expression to maintain their CSC phenotype.

The dynamics of shapes of vesicle membranes with time dependent spontaneous curvature.

We study the time evolution of the shape of a vesicle membrane under time-dependent spontaneous curvature by means of phase-field model. We introduce the variation in time of the spontaneous curvature via a second field which represents the concentration of a substance that anchors with the lipid bilayer thus changing the local curvature and producing constriction. This constriction is mediated by the action on the membrane of an structure resembling the role of a Z ring.

clinical trials for anti-aging therapies.

Therapeutic strategies targeting the hallmarks of aging can be broadly grouped into four categories, namely systemic (blood) factors, metabolic manipulation (diet regimens and dietary restriction mimetics), suppression of cellular senescence (senolytics), and cellular reprogramming, which likely have common characteristics and mechanisms of action. In evaluating the potential synergism of combining such strategies, however, we should consider the possibility of constraining trade-off phenotypes such as impairment in wound healing and immune response, tissue dysfunction and tumorigenesis. Moreover, we are rapidly learning that the benefit/risk ratio of aging-targeted interventions largely depends on intra- and inter-individual variations of susceptibility to the healthspan-, resilience-, and/or lifespan-promoting effects of the interventions.

Age Structure Can Account for Delayed Logistic Proliferation of Scratch Assays.

Scratch assays are in vitro methods for studying cell migration. In these experiments, a scratch is made on a cell monolayer and recolonisation of the scratched region is imaged to quantify cell migration rates. Typically, scratch assays are modelled by reaction diffusion equations depicting cell migration by Fickian diffusion and proliferation by a logistic term.

A multiscale model of epigenetic heterogeneity-driven cell fate decision-making.

The inherent capacity of somatic cells to switch their phenotypic status in response to damage stimuli in vivo might have a pivotal role in ageing and cancer. However, how the entry-exit mechanisms of phenotype reprogramming are established remains poorly understood. In an attempt to elucidate such mechanisms, we herein introduce a stochastic model of combined epigenetic regulation (ER)-gene regulatory network (GRN) to study the plastic phenotypic behaviours driven by ER heterogeneity.

In vitro cell migration quantification method for scratch assays.

The scratch assay is an in vitro technique used to assess the contribution of molecular and cellular mechanisms to cell migration. The assay can also be used to evaluate therapeutic compounds before clinical use. Current quantification methods of scratch assays deal poorly with irregular cell-free areas and crooked leading edges which are features typically present in the experimental data.

Viral replication modes in single-peak fitness landscapes: A dynamical systems analysis.

Positive-sense, single-stranded RNA viruses are important pathogens infecting almost all types of organisms. Experimental evidence from distributions of mutations and from viral RNA amplification suggest that these pathogens may follow different RNA replication modes, ranging from the stamping machine replication (SMR) to the geometric replication (GR) mode. Although previous theoretical work has focused on the evolutionary dynamics of RNA viruses amplifying their genomes with different strategies, little is known in terms of the bifurcations and transitions involving the so-called error threshold (mutation-induced dominance of mutants) and lethal mutagenesis (extinction of all sequences due to mutation accumulation and demographic stochasticity).

Mitostemness.

Unraveling the key mechanisms governing the retention versus loss of the cancer stem cell (CSC) state would open new therapeutic avenues to eradicate cancer. Mitochondria are increasingly recognized key drivers in the origin and development of CSC functional traits. We here propose the new term "mitostemness" to designate the mitochondria-dependent signaling functions that, evolutionary rooted in the bacterial origin of mitochondria, regulate the maintenance of CSC self-renewal and resistance to differentiation.

Noise-induced bistability in the quasi-neutral coexistence of viral RNAs under different replication modes.

Evolutionary and dynamical investigations into real viral populations indicate that RNA replication can range between the two extremes represented by so-called 'stamping machine replication' (SMR) and 'geometric replication' (GR). The impact of asymmetries in replication for single-stranded (+) sense RNA viruses has been mainly studied with deterministic models. However, viral replication should be better described by including stochasticity, as the cell infection process is typically initiated with a very small number of RNA macromolecules, and thus largely influenced by intrinsic noise.

Minimum Action Path Theory Reveals the Details of Stochastic Transitions Out of Oscillatory States.

Cell state determination is the outcome of intrinsically stochastic biochemical reactions. Transitions between such states are studied as noise-driven escape problems in the chemical species space. Escape can occur via multiple possible multidimensional paths, with probabilities depending nonlocally on the noise.

Epigenetic regulation of cell fate reprogramming in aging and disease: A predictive computational model.

Understanding the control of epigenetic regulation is key to explain and modify the aging process. Because histone-modifying enzymes are sensitive to shifts in availability of cofactors (e.g.

Noise-induced bistability in the fate of cancer phenotypic quasispecies: a bit-strings approach.

Tumor cell populations are highly heterogeneous. Such heterogeneity, both at genotypic and phenotypic levels, is a key feature during tumorigenesis. How to investigate the impact of this heterogeneity in the dynamics of tumors cells becomes an important issue.