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Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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53 records · Page 3

Complex of human Melanotransferrin and SC57.32 Fab fragment reveals novel interdomain arrangement with ferric N-lobe and open C-lobe

Melanotransferrin (MTf) is an iron-binding member of the transferrin superfamily that can be membrane-anchored or secreted in serum. On cells, it can mediate transferrin-independent iron uptake and promote proliferation. In serum, it is a transcytotic iron transporter across the blood–brain barrier. MTf has been exploited as a drug delivery carrier to the brain and as an antibody-drug conjugate (ADC) target due to its oncogenic role in melanoma and its elevated expression in triple-negative breast cancer (TNBC). For treatment of TNBC, an MTf-targeting ADC completed a phase I clinical trial (NCT03316794). The structure of its murine, unconjugated Fab fragment (SC57.32) is revealed here in complex with MTf. The MTf N-lobe is in an active and iron-bound, closed conformation while the C-lobe is in an open conformation incompatible with iron binding. This combination of active and inactive domains displays a novel inter-domain arrangement in which the C2 subdomain angles away from the N-lobe. The C2 subdomain also contains the SC57.32 glyco-epitope, which comprises ten protein residues and two N-acetylglucosamines. Our report reveals novel features of MTf and provides a point of reference for MTf-targeting, structure-guided drug design.

59 BASIC BIOLOGICAL SCIENCES↗

Paclitaxel loading in cationic liposome vectors is enhanced by replacement of oleoyl with linoleoyl tails with distinct lipid shapes

Abstract Lipid carriers of hydrophobic paclitaxel (PTX) are used in clinical trials for cancer chemotherapy. Improving their loading capacity requires enhanced PTX solubilization. We compared the time-dependence of PTX membrane solubility as a function of PTX content in cationic liposomes (CLs) with lipid tails containing one (oleoyl; DOPC/DOTAP) or two (linoleoyl; DLinPC/newly synthesized DLinTAP) cis double bonds by using microscopy to generate kinetic phase diagrams. The DLin lipids displayed significantly increased PTX membrane solubility over DO lipids. Remarkably, 8 mol% PTX in DLinTAP/DLinPC CLs remained soluble for approximately as long as 3 mol% PTX (the solubility limit, which has been the focus of most previous studies and clinical trials) in DOTAP/DOPC CLs. The increase in solubility is likely caused by enhanced molecular affinity between lipid tails and PTX, rather than by the transition in membrane structure from bilayers to inverse cylindrical micelles observed with small-angle X-ray scattering. Importantly, the efficacy of PTX-loaded CLs against prostate cancer cells (their IC50 of PTX cytotoxicity) was unaffected by changing the lipid tails, and toxicity of the CL carrier was negligible. Moreover, efficacy was approximately doubled against melanoma cells for PTX-loaded DLinTAP/DLinPC over DOTAP/DOPC CLs. Our findings demonstrate the potential of chemical modifications of the lipid tails to increase the PTX membrane loading while maintaining (and in some cases even increasing) the efficacy of CLs. The increased PTX solubility will aid the development of liposomal PTX carriers that require significantly less lipid to deliver a given amount of PTX, reducing side effects and costs.

36 MATERIALS SCIENCE↗

Structural elucidation of polydopamine facilitated by ionic liquid solvation

Minimal understanding of the formation mechanism and structure of polydopamine (pDA) and its natural analogue, eumelanin, impedes the practical application of these versatile polymers and limits our knowledge of the origin of melanoma. The lack of conclusive structural evidence stems from the insolubility of these materials, which has spawned significantly diverse suggestions of pDA's structure in the literature. We discovered that pDA is soluble in certain ionic liquids. Using these ionic liquids (ILs) as solvents, we present an experimental methodology to solvate pDA, enabling us to identify pDA's chemical structure. The resolved pDA structure consists of self-assembled supramolecular aggregates that contribute to the increasing complexity of the polymer. The underlying molecular energetics of pDA solvation and a macroscopic picture of the disruption of the aggregates using IL solvents have been investigated, along with studies of the aggregation mechanism in water.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

Engineering endosomolytic nanocarriers of diverse morphologies using confined impingement jet mixing

The clinical translation of many biomolecular therapeutics has been hindered by undesirable pharmacokinetic (PK) properties, inadequate membrane permeability, poor endosomal escape and cytosolic delivery, and/or susceptibility to degradation. Overcoming these challenges merits the development of nanoscale drug carriers (nanocarriers) to improve the delivery of therapeutic cargo. Herein, we implement a flash nanoprecipitation (FNP) approach to produce nanocarriers of diverse vesicular morphologies by using various molecular weight PEG-bl-DEAEMA-co-BMA (PEG-DB) polymers. We demonstrated that FNP can produce uniform (PDI < 0.1) particles after 5 impingements, and that by varying the copolymer hydrophilic mass fraction, FNP enables access to a diverse variety of nanoarchitectures including micelles, unilamellar vesicles (polymersomes), and multi-compartment vesicles (MCVs). We synthesized a library of 2 kDa PEG block copolymers, with DEAEMA-co-BMA second block molecular weights of 3, 6, 12, 15, 20, and 30 kDa. All formulations were both pH responsive, endosomolytic, and capable of loading and cytosolically delivering small negatively charged molecules – albeit to different degrees. Using a B16.F10 melanoma model, we showcased the therapeutic potential of a lead FNP formulated PEG-DB nanocarrier, encapsulating the cyclic dinucleotide (CDN) cGAMP to activate the stimulator of interferon genes (STING) pathway in a therapeutically relevant context. Collectively, these data demonstrate that an FNP process can be used to formulate pH-responsive nanocarriers of diverse morphologies using a PEG-DB polymer system. As FNP is an industrially scalable process, these data address the critical translational challenge of producing PEG-DB nanoparticles at scale. Furthermore, the diverse morphologies produced may specialize in the delivery of distinct biomolecular cargos for other therapeutic applications, implicating the therapeutic potential of this platform in an array of disease applications.

36 MATERIALS SCIENCE↗

Ultrasound controlled mechanophore activation in hydrogels for cancer therapy

Significance Biomedical application of mechanophores is the next frontier in polymer mechanochemistry. We report the concept, mechanochemical dynamic therapy (MDT), that utilizes remote, ultrasound-triggered mechanophore activation to enable anticancer activities. We selected an azo-based mechanophore to generate reactive free radicals (FRs) under the control of high-intensity focused ultrasound (HIFU), which subsequently produced ROS. We investigated two sets of in vitro mouse cancer models: 1) melanoma (B16F10) and 2) breast cancer (E0771). Inhibition of growth and decreases in viabilities of both B16F10 and E0771 were observed in correlation to the release of ROS by mechanophore activation. By circumventing the known issues in photodynamic therapy and sonodynamic therapy, we anticipate MDT to be a powerful anticancer tool complementary to other existing cancer treatments.

60 APPLIED LIFE SCIENCES↗

Discovery of highly potent and ALK2/ALK1 selective kinase inhibitors using DNA-encoded chemistry technology

Activin receptor type 1 (ACVR1; ALK2) and activin receptor like type 1 (ACVRL1; ALK1) are transforming growth factor beta family receptors that integrate extracellular signals of bone morphogenic proteins (BMPs) and activins into Mothers Against Decapentaplegic homolog 1/5 (SMAD1/SMAD5) signaling complexes. Several activating mutations in ALK2 are implicated in fibrodysplasia ossificans progressiva (FOP), diffuse intrinsic pontine gliomas, and ependymomas. The ALK2 R206H mutation is also present in a subset of endometrial tumors, melanomas, non-small lung cancers, and colorectal cancers, and ALK2 expression is elevated in pancreatic cancer. Using DNA-encoded chemistry technology, we screened 3.94 billion unique compounds from our diverse DNA-encoded chemical libraries (DECLs) against the kinase domain of ALK2. Off-DNA synthesis of DECL hits and biochemical validation revealed nanomolar potent ALK2 inhibitors. Further structure-activity relationship studies yielded center for drug discovery (CDD)-2789, a potent [NanoBRET (NB) cell IC50: 0.54 μM] and metabolically stable analog with good pharmacological profile. Crystal structures of ALK2 bound with CDD-2281, CDD-2282, or CDD-2789 show that these inhibitors bind the active site through Van der Waals interactions and solvent-mediated hydrogen bonds. CDD-2789 exhibits high selectivity toward ALK2/ALK1 in KINOMEscan analysis and NB K192 assay. In cell-based studies, ALK2 inhibitors effectively attenuated activin A and BMP-induced Phosphorylated SMAD1/5 activation in fibroblasts from individuals with FOP in a dose-dependent manner. Thus, CDD-2789 is a valuable tool compound for further investigation of the biological functions of ALK2 and ALK1 and the therapeutic potential of specific inhibition of ALK2.

Jimmidi, Ravikumar↗

Discovery of an Antarctic Ascidian-Associated Uncultivated Verrucomicrobia with Antimelanoma Palmerolide Biosynthetic Potential

The Antarctic marine ecosystem harbors a wealth of biological and chemical innovation that has risen in concert over millennia since the isolation of the continent and formation of the Antarctic circumpolar current. Scientific inquiry into the novelty of marine natural products produced by Antarctic benthic invertebrates led to the discovery of a bioactive macrolide, palmerolide A, that has specific activity against melanoma and holds considerable promise as an anticancer therapeutic. While this compound was isolated from the Antarctic ascidian Synoicum adareanum, its biosynthesis has since been hypothesized to be microbially mediated, given structural similarities to microbially produced hybrid nonribosomal peptide-polyketide macrolides. Here, we describe a metagenome-enabled investigation aimed at identifying the biosynthetic gene cluster (BGC) and palmerolide A-producing organism. A 74-kbp candidate BGC encoding the multimodular enzymatic machinery (hybrid type I-trans-AT polyketide synthase-nonribosomal peptide synthetase and tailoring functional domains) was identified and found to harbor key features predicted as necessary for palmerolide A biosynthesis. Surveys of ascidian microbiome samples targeting the candidate BGC revealed a high correlation between palmerolide gene targets and a single 16S rRNA gene variant (R = 0.83 to 0.99). Through repeated rounds of metagenome sequencing followed by binning contigs into metagenome-assembled genomes, we were able to retrieve a nearly complete genome (10 contigs) of the BGC-producing organism, a novel verrucomicrobium within the Opitutaceae family that we propose here as “Candidatus Synoicihabitans palmerolidicus.” The refined genome assembly harbors five highly similar BGC copies, along with structural and functional features that shed light on the host-associated nature of this unique bacterium.

59 BASIC BIOLOGICAL SCIENCES↗

Mathematical model of a personalized neoantigen cancer vaccine and the human immune system

Cancer vaccines are an important component of the cancer immunotherapy toolkit enhancing immune response to malignant cells by activating CD4 + and CD8 + T cells. Multiple successful clinical applications of cancer vaccines have shown good safety and efficacy. Despite the notable progress, significant challenges remain in obtaining consistent immune responses across heterogeneous patient populations, as well as various cancers. We present a mechanistic mathematical model describing key interactions of a personalized neoantigen cancer vaccine with an individual patient’s immune system. Specifically, the model considers the vaccine concentration of tumor-specific antigen peptides and adjuvant, the patient’s major histocompatibility complexes I and II copy numbers, tumor size, T cells, and antigen presenting cells. We parametrized the model using patient-specific data from a clinical study in which individualized cancer vaccines were used to treat six melanoma patients. Model simulations predicted both immune responses, represented by T cell counts, to the vaccine as well as clinical outcome (determined as change of tumor size). This model, although complex, can be used to describe, simulate, and predict the behavior of the human immune system to a personalized cancer vaccine.

60 APPLIED LIFE SCIENCES↗

Utilizing CellBox to Describe Varied Dynamical Systems

CellBox is a hybrid modeling framework that integrates machine-learning approaches with explicit mathematical modeling to determine the behavior of dynamical systems, intended for determining the complex interactions of molecule and phenotype within a cellular environment using perturbation/response-based data. The original work utilized analysis of a melanoma cell line, SK-Mel-133, which we sought to expand to and evaluate effectiveness in describing other nonlinear systems both within and outside of biology. We evaluated with two models. One model is based upon the free-fall of an object under a velocity-dependent drag force; this produced inherent perturbation/response data. The other model is based upon a form of mass-action molecular kinetics; for this, we ran the simulation to steady state in each species for each perturbation and select the steady state as input for CellBox. We determined that CellBox, outside of its original use case, can still strongly predict even non-biological dynamical systems in the small-perturbation regime, with r = 0.99977 to 0.85123, p < 0.05 for freefall. However, CellBox cannot accurately predict behavior within large-perturbation regimes, p >> 0.05 for freefall. In addition, we performed a naïve comparison of CellBox network structure to known network structure in the mass-action model to assess accuracy.

97 MATHEMATICS AND COMPUTING↗

Transient histone deacetylase inhibition reveals cell type invariant and specific effects of chromatin decondensation on irradiation response

Radiation therapy plays a prominent role in breast cancer treatment, but the high doses of radiation damage both healthy and cancerous cells. Therefore, additional research is needed into combination therapies that could preferentially radiosensitize cancer cells compared to surrounding healthy tissue without causing deleterious side effects. Histone deacetylase inhibitor drugs (HDACis) have been tested as radiosensitizers in both basic research and clinical trials, but the long exposure time typically used in these treatments and the lack of matched healthy cell controls often leave aspects of their mechanism of action unclear. Here, we show that transient (2 h) trichostatin A (TSA) treatment of cancerous and non-tumorigenic breast epithelial cell lines increases immediate DNA damage and decreases long term cell viability in both cell types at high radiation doses. Transient TSA treatment also causes an increase in DNA damage signals after 5 Gy X-rays in other cancer and healthy cell types: A375 melanoma cells and BJ5-ta fibroblasts. This suggests that chromatin decompaction acts to increase cellular vulnerability to initial DNA damage from high doses of radiation in a cell type independent manner that does not rely on changes to DNA repair pathways caused by longer TSA treatment. However, responses to lower doses of radiation and long term survival are more cell type specific: only MCF7 cells experience an effect of TSA on DNA damage after 1 Gy X-ray radiation while MCF10a cells experience somewhat more evident cell viability effects of combined TSA and radiation treatment long term.

Li, Heng [Biochemistry & Cellular and Molecular Bi↗

Bioinformatic and Mechanistic Analysis of the Palmerolide PKS-NRPS Biosynthetic Pathway From the Microbiome of an Antarctic Ascidian

Complex interactions exist between microbiomes and their hosts. Increasingly, defensive metabolites that have been attributed to host biosynthetic capability are now being recognized as products of host-associated microbes. These unique metabolites often have bioactivity targets in human disease and can be purposed as pharmaceuticals. Polyketides are a complex family of natural products that often serve as defensive metabolites for competitive or pro-survival purposes for the producing organism, while demonstrating bioactivity in human diseases as cholesterol lowering agents, anti-infectives, and anti-tumor agents. Marine invertebrates and microbes are a rich source of polyketides. Palmerolide A, a polyketide isolated from the Antarctic ascidian Synoicum adareanum, is a vacuolar-ATPase inhibitor with potent bioactivity against melanoma cell lines. The biosynthetic gene clusters (BGCs) responsible for production of secondary metabolites are encoded in the genomes of the producers as discrete genomic elements. A candidate palmerolide BGC was identified from a S. adareanum microbiome-metagenome based on a high degree of congruence with a chemical structure-based retrobiosynthetic prediction. Protein family homology analysis, conserved domain searches, active site and motif identification were used to identify and propose the function of the ~75 kbp trans-acyltransferase (AT) polyketide synthase-non-ribosomal synthase (PKS-NRPS) domains responsible for the stepwise synthesis of palmerolide A. Though PKS systems often act in a predictable co-linear sequence, this BGC includes multiple trans-acting enzymatic domains, a non-canonical condensation termination domain, a bacterial luciferase-like monooxygenase (LLM), and is found in multiple copies within the metagenome-assembled genome (MAG). Detailed inspection of the five highly similar pal BGC copies suggests the potential for biosynthesis of other members of the palmerolide chemical family. This is the first delineation of a biosynthetic gene cluster from an Antarctic microbial species, recently proposed as Candidatus Synoicihabitans palmerolidicus. These findings have relevance for fundamental knowledge of PKS combinatorial biosynthesis and could enhance drug development efforts of palmerolide A through heterologous gene expression.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

Uncovering the Core Microbiome and Distribution of Palmerolide in Synoicum adareanum Across the Anvers Island Archipelago, Antarctica

Polar marine ecosystems hold the potential for bioactive compound biodiscovery, based on their untapped macro- and microorganism diversity. Characterization of polar benthic marine invertebrate-associated microbiomes is limited to few studies. This study was motivated by our interest in better understanding the microbiome structure and composition of the ascidian, Synoicum adareanum, in which palmerolide A (PalA), a bioactive macrolide with specificity against melanoma, was isolated. PalA bears structural resemblance to a hybrid nonribosomal peptide-polyketide that has similarities to microbially-produced macrolides. We conducted a spatial survey to assess both PalA levels and microbiome composition in S. adareanum in a region of the Antarctic Peninsula near Anvers Island (64°46' S, 64°03' W). PalA was ubiquitous and abundant across a collection of 21 ascidians (3 subsamples each) sampled from seven sites across the Anvers Island Archipelago. The microbiome composition (V3–V4 16S rRNA gene sequence variants) of these 63 samples revealed a core suite of 21 bacterial amplicon sequence variants (ASVs)—20 of which were distinct from regional bacterioplankton. ASV co-occurrence analysis across all 63 samples yielded subgroups of taxa that may be interacting biologically (interacting subsystems) and, although the levels of PalA detected were not found to correlate with specific sequence variants, the core members appeared to occur in a preferred optimum and tolerance range of PalA levels. These results, together with an analysis of the biosynthetic potential of related microbiome taxa, describe a conserved, high-latitude core microbiome with unique composition and substantial promise for natural product biosynthesis that likely influences the ecology of the holobiont.

59 BASIC BIOLOGICAL SCIENCES↗

Measuring the metastatic potential of cancer cells

Cancer cells must secrete proteolytic enzymes to invade adjacent tissues and migrate to a new metastatic site. Urokinase (uPA) is a key enzyme related to metastasis in cancers of the lung, colon, gastric, uterine, breast, brain, and malignant melanoma. A NASA technology utilization project has combined fluorescence microscopy, image analysis, and flow cytometry, using fluorescent dyes, and urokinase-specific antibodies to measure uPA and abnormal DNA levels (related to cancer cell proliferation) inside the cancer cells. The project is focused on developing quantitative measurements to determine if a patient's tumor cells are actively metastasizing. If a significant number of tumor cells contain large amounts of uPA (esp. membrane-bound) then the post-surgical chemotherapy or radiotherapy can be targeted for metastatic cells that have already left the primary tumor. These analytical methods have been applied to a retrospective study of biopsy tissues from 150 node negative, stage 1 breast cancer patients. Cytopathology and image analysis has shown that uPA is present in high levels in many breast cancer cells, but not found in normal breast. Significant amounts of uPA also have been measured in glioma cell lines cultured from brain tumors. Commercial applications include new diagnostic tests for metastatic cells, in different cancers, which are being developed with a company that provides a medical testing service using flow cytometry for DNA analysis and hormone receptors on tumor cells from patient biopsies. This research also may provide the basis for developing a new 'magic bullet' treatment against metastasis using chemotherapeutic drugs or radioisotopes attached to urokinase-specific monoclonal antibodies that will only bind to metastatic cells.

Morrison, Dennis R.↗

Particle irradiation induces FGF2 expression in normal human lens cells

Particle Irradiation Induces FGF2 Expression in Normal Human Lens Cells. Particle radiations, including both proton and helium-ion beams, have been used to successfully treat choroidal melanoma, but with the complication of radiation-induced cataract. We have investigated a role for radiation-induced changes in the expression of basic fibroblast growth factor (FGF2) gene expression as part of the mechanism(s) underlying lens cell injury associated with cataract. Normal human lens epithelial (HLE) cells were cultured in vitro on extracellular matrix (ECM) originated from bovine corneal endothelial cells. This study reports evidence for rapid but transient induction of FGF2 transcripts, an increase of between 5- and 8-fold, within 0.5 h after exposure to particle radiation, followed by another wave of increased transcription at 2-3 h postirradiation. Immunofluorescence results confirm the enhanced levels of FGF2 protein rapidly after exposure to protons or helium ions, followed by another wave of increased activity unique to helium at 6 h postirradiation. This second wave of increased immunoreactivity was not observed in the proton-irradiated samples. Total FGF2 protein analysis after helium-ion exposures shows induced expression of three FGF2 isoforms, with an increase of up to 2-fold in the 18-kDa low-molecular-weight species. Studies of the effects of protons on individual FGF2 protein isoforms are in progress. Several mechanisms involving a role for FGF2 in radiation-induced cataract are discussed.

NASA Discipline Radiation Health↗

Assessing Long-Term Health (LTH) Outcomes in Astronauts

NASA has linked potential Long-Term Health (LTH) risks of astronauts to their spaceflight experience, including the effects of space radiation, microgravity, and stressors such as isolation, sleep deprivation, and stress. Therefore, assessing the LTH outcomes for astronauts exposed to these hazards becomes a critical investigation in ensuring any deleterious effects are minimal. Prior research conducted into LTH outcomes of astronauts has not revealed increases in non-accidental mortality rates when compared to the U.S. general population, analog healthy cohorts, and professional athletes. One study did report an increased incidence of non-fatal cardiovascular disease events (Hazard Ratio=2.41, 95% Confidence Interval 1.26 to 4.63). Additional evidence indicates that astronauts may have increases in incidences of melanoma, prostate, and hematologic cancers, though the former is consistent with rates observed among aircraft pilots and the latter two are likely caused by detection bias due to increased screening on former astronauts.

long term health↗

Long-Term Health Risk Quantification

Astronauts face hazards during spaceflight, including space radiation exposure, isolation and confinement, traveling far distances from Earth, reduced gravity levels, and closed and hostile environments. These hazards drive the definition of human health and performance risks associated with spaceflight. NASA’s Human System Risk Board maintains the human spaceflight risk posture for in-mission risks, as well as post-flight, Long-Term Health (LTH)risks potentially occurring later in the astronaut’s life. LTH risk encompasses the timeframe from immediately post-flight, through the rest of an astronaut’s career, through retirement, and until death. Possible LTH risk outcomes include the time and interventions needed for the astronaut to return to preflight physiological states after experiencing spaceflight hazards and recovery from any in-mission medical events that persist into the post-flight timeframe. It includes chronic complications that may arise due to experiencing in-flight medical conditions or injuries and medical conditions that occur later in life with a higher probability of occurrence or with more severity because of their spaceflight exposure. Finally, LTH risk outcomes can also include a reduction in life expectancy due to spaceflight exposures. There have been 144 medical conditions identified by NASA’s Lifetime Surveillance of Astronaut Health team to be associated with LTH risk. Epidemiological studies have been performed for some of these conditions to determine if astronauts suffer from an increased prevalence or severity of the condition due to their spaceflight experience compared to a comparable cohort .Differences in astronaut mortality or morbidity due to spaceflight experience were not detected in several of these studies. There were two cases where a modest increase in the incidence rate of astronaut LTH outcomes was detected. The first suggested an increase in the incidence of melanoma cases in astronauts, where the number of cases in astronauts were similar to the elevated number of cases observed in airplane pilots. The second provided some evidence of elevated numbers of cardiovascular disease events in astronauts compared to an appropriate healthy comparator cohort, which may warrant additional investigation. The lack of detection of LTH risk outcomes should not ease concerns about astronaut LTH. The studies highlighted here constitute only a small portion of the potential LTH conditions that could occur. Once epidemiological studies are performed on all conditions, significant findings may be detected. The analysis of astronaut LTH also suffers from limited numbers of data points because of the limited numbers of astronauts overall and the even fewer who have reached an age where LTH outcomes may begin to manifest. As shuttle and ISS astronauts begin to age and increase the feasibility of analysis, LTH outcomes may be detected. An application of risk quantification is the use of risk metrics within trade studies for resource prioritization and decision making. Trade studies regarding countermeasures to LTH risk outcomes would benefit from a quantification of LTH risk. NASA has ground-based processes in place such as astronaut screening and access to continuous medical monitoring and care during and after their astronaut career which are the main methods for mitigating LTH risk. In-mission countermeasures, such as acceptable levels of medical care and available countermeasures to counter spaceflight related physiological decrements, can mitigate a poor health and performance status immediately post-flight. Identifying appropriate risk metrics, obtaining valid quantities for them, and tying them to LTH countermeasures are necessary steps for realizing their use in trade studies. This presentation will highlight the challenges associated with the identification, quantification, and utilization of LTH risk metrics

Beth Lewandowski↗

Tensile stress stimulates microtubule outgrowth in living cells

Cell motility is driven by the sum of asymmetric traction forces exerted on the substrate through adhesion foci that interface with the actin cytoskeleton. Establishment of this asymmetry involves microtubules, which exert a destabilising effect on adhesion foci via targeting events. Here, we demonstrate the existence of a mechano-sensing mechanism that signals microtubule polymerisation and guidance of the microtubules towards adhesion sites under increased stress. Stress was applied either by manipulating the body of cells moving on glass with a microneedle or by stretching a flexible substrate that cells were migrating on. We propose a model for this mechano-sensing phenomenon whereby microtubule polymerisation is stimulated and guided through the interaction of a microtubule tip complex with actin filaments under tension.

NASA Discipline Cell Biology↗